Sanitizing Agents For Virus Inactivation and Disinfection

Received: 13 March 2020 Revised: 2 April 2020 Accepted: 5 April 2020
DOI: 10.1002/viw2.16
REVIEW
Sanitizing agents for virus inactivation and disinfection
Qianyu Lin2 Jason Y. C. Lim1 Kun Xue1 Pek Yin Michelle Yew1 Cally Owh1
Pei Lin Chee1 Xian Jun Loh1
1 SoftMaterials Department, Institution of

Abstract
Materials Research and Engineering, Agency
for Science, Technology and Research Viral epidemics develop from the emergence of new variants of infectious viruses.
(A*STAR), Innovis, Singapore The lack of effective antiviral treatments for the new viral infections coupled with
2 NUS Graduate School for Integrative rapid community spread of the infection often result in major human and financial
Sciences and Engineering, National
University of Singapore, Singapore loss. Viral transmissions can occur via close human-to-human contact or via contact-
ing a contaminated surface. Thus, careful disinfection or sanitization is essential to
Correspondence
curtail viral spread. A myriad of disinfectants/sanitizing agents/biocidal agents are
Xian Jun Loh, Soft Materials Department,
Institution of Materials Research and Engi- available that can inactivate viruses, but their effectiveness is dependent upon many
neering, Agency for Science, Technology and factors such as concentration of agent, reaction time, temperature, and organic load. In
Research (A*STAR), 2 Fusionopolis Way,
this work, we review common commercially available disinfectants agents available
Innovis, Singapore 138634
Email: lohxj@imre.a-star.edu.sg on the market and evaluate their effectiveness under various application conditions.
Jason Y. C. Lim, Soft Materials Department, In addition, this work also seeks to debunk common myths about viral inactivation
Institution of Materials Research and Engi-
neering, Agency for Science, Technology and
and highlight new exciting advances in the development of potential sanitizing
Research (A*STAR), 2 Fusionopolis Way, agents.
Innovis, Singapore 138634
Email: jason_lim@imre.a-star.edu.sg KEYWORDS
disinfectant, sanitizer, surface, virucidal, virus
1 I N T RO D U C T I O N catastrophe, with more than 50 million deaths and 500 million

infections.2 A similar pandemic today will undoubtedly result
Viral transmissions and infections have posed severe threats in even more disastrous outcomes.3 At the time of writing
to human health and well-being throughout history, and have in early April 2020, the novel coronavirus causing Covid-19
led to widespread socioeconomic disruptions. During the (SARS-CoV-2, or formerly known as HCoV-19), which was
2014 Ebola pandemic in West Africa, the gross domestic first reported by China in late 2019, has resulted in more than
product (GDP) growth of Liberia, one of the worst-affected a million confirmed cases of infections and almost 57,000
countries, fell from 8.7% in 2013 to just 0.7% in 2014.1 Bol- fatalities worldwide.4 This is the largest coronavirus outbreak
stered by the close-knit global connectivity we enjoy today, in human populations within the first 20 years of the 21st
the threat of a global virus pandemic is greater now than any century, occurring on a larger scale than the earlier outbreaks
other time in human history, as viruses can spread across the of Severe Acute Respiratory Syndrome (SARS) and Middle
globe at unprecedented rates. Even a century ago in 1918, the East Respiratory Syndrome (MERS) in 2002–2004 and 2012,
“Spanish influenza” pandemic caused a worldwide healthcare respectively.5 While government interventions can influence
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2020 The Authors. VIEW published by John Wiley & Sons Australia, Ltd and Shanghai Fuji Technology Consulting Co., Ltd, authorized by Professional Community of Experimental
Medicine, National Association of Health Industry and Enterprise Management (PCEM)
VIEW. 2020;1:e16. wileyonlinelibrary.com/journal/viw2 1 of 26

https://doi.org/10.1002/viw2.16
2 of 26 LIN ET AL.
the rates and range of outbreaks,6 individuals can play Table 1). This is exacerbated by the lack of effective treatment
equally, or arguably even more important roles in limiting against several of these viruses.
the spread of viruses in the public and healthcare arenas.7
Human-to-human transmission of common influenza viruses
and coronaviruses can occur through virus-laden body fluids, 2.2 Surfaces spread viruses
as well as self-innoculation of the mucous membranes in the
nose, mouth, or eyes by touching contaminated dry surfaces.8 Surfaces, including our hands, play an important part in the
Depending on the type of surface and ambient conditions, spread of viruses. Viruses such as poliovirus and bacterio-
viruses can persist for as short as <5 min to greater than phage showed a much higher survival when they were trans-
28 days on inanimate surfaces.9 The use of sanitizing agents ferred by direct contact of surfaces, as opposed to droplet
for personal care and surface disinfection are clearly of aerosolization or dust containing viruses.14 Hand-to-surface
paramount importance in limiting viral transmissions, by contact of only 5 s was sufficient to transfer a significant pro-
inactivating the viruses before they have a chance to enter the portion of the virus, and viruses could then spread by touch-
human body. ing the mucosa of the nose or conjunctiva of the eye.15 The
In this review, we summarize the various types of sanitiz- chance of spread is in turn directly correlated with the viral
ing agents used in commercially available formulations sci- survival time on the surface, which shows considerable vari-
entifically demonstrated for their virucidal properties to inac- ation between different viruses. For example, among differ-
tivate viruses in suspension and on surfaces. Viruses that ent soft surfaces tested, enteric viruses were shown to sur-
require vectors for transmission, such as the chikungunya and vive on wool blankets for the longest period of time, poster
dengue viruses, are not considered. These “virucidal” agents card for the shortest period of time, and cotton fabric for
can either destroy viruses or alter their surface structures to an intermediate period of time.13 A very recent study has
prevent them from infecting potential host cells (Section 2). found that the Covid-19 coronavirus (SARS-CoV-2) can per-
They differ from “antiviral” compounds10 which inhibits sist longest on propylene plastic surfaces and stainless steel,
virus replication in host cells. The effective dose of each san- with viable viruses found up to 72 hr after initial application
itizing agent, exposure time for effective virucidal activity, though at a greatly reduced viral titer.16 Much shorter persis-
suitability for usage under domestic or healthcare/hospital tence was observed on copper surfaces, with no viable viruses
settings and mechanisms of action are considered. We also observed after 4 hr. While the closely-related SARS-CoV-
explore what has been scientifically shown for some common 1 coronavirus showed no significant statistical differences in
myths believed to inactivate viruses and prevent their spread. half-life on these surfaces, SARS-CoV-2 could persist consid-
Finally, we present promising new research directions, mate- erably longer on cardboard surfaces: 24 hr were required for
rials, and strategies that have been shown to inactivate viruses no viable SARS-CoV-2 to be detected, compared with just 8
but have yet to reach widespread commercial availability. hr for SARS-CoV-1.
2 G E N E R A L WOR K I NG 2.3 Factors affecting disinfectant efficacy

PRINCIPLES OF DISINFECTANTS
AGA I N ST V I RU S E S The main measure of efficacy of the disinfectant is by the fold
reduction in infectivity of the virus, and this is typically con-
2.1 Viruses and infectivity ducted by carrier tests and suspension tests. The key param-
eters that affect the efficacy of disinfection agents against
Viruses are typically composed of a viral capsid containing viruses include the contact time, concentration of disinfec-
nucleic acids inside. The nucleic acid serve as the template tion agent, and the particular virus involved.17 The disinfec-
information for replication, while the capsid and its associ- tion inactivation can be described by modified forms of the
ated proteins function both to protect the nucleic acid and bind Chick–Watson law:
to host cell receptors.11 The coronavirus SARS-CoV-2, for
𝑁
example, uses the spike glycoprotein to bind to host cell sialic log = −k𝐶𝑇
𝑁𝑜
acid receptors.12 Outside of a host cell, viruses are unable
to replicate and increase in number. However, they can often where No is the original number of microbes, N is the final
survive for long periods of time in this state.13 When they number of microbes, C is the disinfectant concentration, T
encounter a suitable host cell, they will infect and enter the is the contact time, and k is the inactivation rate constant
host cell, hijacking the cellular machinery for its own repli- (specific to the microbe).18 With a decrease in the concentra-
cation. Viruses are able to infect cells, including even bacte- tion of the active disinfecting ingredient, the contact time will
rial cells, and cause a range of commonly seen diseases (see likely need to be increased to achieve adequate disinfection.19
LIN ET AL. 3 of 26
TABLE 1 Viruses and common diseases

Name of virus Category of disease Disease
Influenza Respiratory Flu
Coronavirus Respiratory Cold (mostly)
Herpes Simplex virus 2 Sexually transmitted infections Herpes
Human Immunodeficiency virus (HIV) Immune Acquired immune deficiency syndrome (AIDS)
Norovirus Gastrointestinal Vomiting/diarrhea
Hepatitis A virus Gastrointestinal Liver inflammation
Poliovirus Neurological Polio
Adenovirus Respiratory, ocular, gastrointestinal Cold, viral conjunctivitis vomiting, and diarrhea
A reduction of viral infectivity by 4 log units correlates to a structural damage to the phage, including damage to capsid
99.99% reduction in the viral titer. The log unit reduction and proteins.24 However, the disinfectant might also need to
percent (%) reduction are used interchangeably in literature to penetrate to destroy the nucleic acids, as viruses such as polio
describe disinfectant efficacy. retain infectivity with the RNA alone.21 While the enveloped
Disinfection efficacy can also be influenced by environ- virus Influenza H1N1 could be inactivated by all the disin-
mental factors. If disinfection requires chemical reactions to fectants tested,25 it is much more challenging to inactivate
take place, such as for formaldehyde, then the rate of disin- small non-enveloped noroviruses, and several commonly
fection will be higher at higher temperatures. Under cold tem- available disinfectants are not able to sufficiently reduce
peratures, certain disinfectants could be ineffective as the rate infectivity.2627
of disinfection would be exceedingly low.20 Humidity is also Viruses also show resistance to disinfection due to the
another factor that could affect disinfectant penetration to the cellular materials that viruses are normally associated with.
virus. For reactions such as aldehyde disinfectants, a change Viruses are normally reliant on host cells for replication, so
in pH will also affect the disinfectant efficacy.17 they are often found together with material such as cell debris,
soil, and aerosolized droplets.20 These are called viral clump-
ing protective factors, and they can both reduce the pene-
2.4 Factors influencing virus susceptibility tration of the disinfectant to the virus, and can also interact
and reduce the activity of the disinfecting agents. This has a
There are specific unique characteristics of viruses that big impact on the disinfectants, necessitating a much higher
influence inactivation by disinfection. There are three main concentration for effective disinfection. Disinfection is com-
types of viruses with different structures, classified here monly associated with and reliant on cleaning processes, as
according to increasing difficulty of chemical disinfectant the removal of organic material impurities first can allow for
inactivation: enveloped viruses, large unenveloped viruses, a better disinfection process.28 Viruses can also aggregate in
and small unenveloped viruses (see Table 2). Larger viruses the environment, for example, upon exposure to disinfectants,
are generally more sensitive to disinfectants, although there thereby making it more difficult for disinfectants to penetrate
are exceptions.21 A few disinfectant solutions tested were all and access the viruses.29
effective against the enveloped viruses Herpes Simplex Virus
and Human Immunodeficiency Virus (HIV) type 1, although
less effective against the small non-enveloped human cox- 3 COM M ERCIALLY AVA ILABL E
sackie virus.22 Enveloped viruses contain a lipid envelope VIRUCIDA L SANITIZING AGEN T S
that is required for infection, and therefore interfering with the
envelope could potentially reduce virus infectivity. Lipophilic 3.1 Alcohols
disinfectants can often be used to inactivate enveloped
viruses. In contrast, non-enveloped viruses utilize a protein Alcohols, specifically isopropyl alcohol (otherwise known
coat for infection, and therefore inactivation often requires as isopropanol and propan-2-ol) and ethyl alcohol (ethanol),
denaturation of the redundant viral capsid proteins or essential are capable of inactivating a wide spectrum of bacterial,
replicative proteins.23 Disinfectants that disrupt proteins such fungi, and viral activities. These actives play an impor-
as glutaraldehyde or sodium hypochlorite could be effective tant role in the healthcare industry for skin antisepsis and
at inactivating non-enveloped viruses.21 Sodium hypochlorite disinfecting small medical tools. Although it is shown to
was shown to inactivate the bacteriophage PAO1, and further be effective in annihilating infectious microorganisms, alco-
electron microscopy studies showed that there was extensive hols are not sporicidal30,31 and are often coupled with
4 of 26 LIN ET AL.
TABLE 2 Types of common viruses and overall resistance to disinfectants. Table modified from reference21
Type of virus[a] Common examples Resistance to disinfectants
Enveloped Herpes Simplex Virus, Human immunodeficiency virus (HIV), Influenza, Coronavirus Low
Large non-enveloped Adenovirus Medium
Small non-enveloped Poliovirus, coxsackievirus, parvovirus, norovirus High
other major biocidal actives to improve its disinfection Although alcohols are effective in eradicating some types
efficacy.31 of viruses, other disinfectants such as quaternary ammonium
Potent biocidal agents eradicate viruses and bacteria by var- compounds (QAC), glutaraldehyde, and hydrogen peroxide
ious mechanisms such as disrupting the structure of the cell, quickly outshine its performance.30 Therefore, disinfectants
and coagulating and/or denaturing proteins in the microorgan- with alcohol as its main active ingredients are generally not
isms. Although few studies have been done to fully understand used to disinfect critical equipment or environment in the
the biocidal activity of alcohol, it is often believed that alco- healthcare settings.30 The use of isopropyl alcohol is also lim-
hols disrupts the cell membrane and denatures the proteins ited as it only inactivates lipid viruses. This greatly reduces
in general.31,32 Viruses as well as many other microorgan- the capabilities of alcohol as a broader use disinfecting agent.
isms are commonly susceptible to this mode of action. Pre- Because alcohols are flammable liquids, large amounts of
vious studies have reported that with the inclusion of water alcohol will increase the risks and dangers of it as a disinfect-
in the biocidal system, the efficacy of alcohol increases as ing agent. The flash point of a higher concentration of alco-
water would facilitate quicker denaturing of proteins.30,31,33 hol solution is lower than that of a lower concentration.32,40
Additionally, the inclusion of water significantly increase the According to Boyce, 70% ethyl alcohol has a flash point
effectiveness of the alcohols as it delays the evaporation of the at 20.5◦ C, while the flash point of 30% ethyl alcohol is at
alcohol and increase its exposure to viruses and bacteria. 29◦ C.32 Furthermore, prolonged and repeated usage of alco-
Generally, the efficacy of alcohols in eradicating microor- hol compromises the integrity of materials such as plastics and
ganisms is optimum between 60% and 90% by solution in dyes. Materials with constant exposure to alcohol may expe-
water (v/v).30,33 In one of the studies, it was reported that rience discoloration, cracking, and swelling due to the effects
80% ethyl alcohol was effective at eradicating hepatitis B of alcohol. Another difficulty with the use of alcohol is that
virus under 2 min and 70% isopropyl alcohol of that within it evaporates quickly when exposed to air, therefore reducing
10 min.34 However, the virucidal activity of alcohol depends the contact time with the virus. Achieving maximum disinfec-
greatly on its concentration of the actives and the type of test tion is difficult unless the tools are immersed in a bath for a
viruses. Ethyl alcohol is effective against enveloped viruses period of time.
and a few non-enveloped viruses. Studies have shown that Even though the capabilities of alcohol are limited, the
ethyl alcohol inactivates enveloped virus such as herpes and active is still commonly used in various disinfectant proce-
influenza to select non-enveloped viruses such as adenovirus, dures. It is imperative to note that together with other proper-
rhinovirus, and rotavirus.30 Isopropyl alcohol, however, was ties of alcohol, its role as a disinfectant is still irreplaceable.
reported to be effective against enveloped viruses but ineffec- Alcohols are often used as an effective disinfectant for ther-
tive against similar non-enveloped viruses.30 The differential mometer, non-critical tools, and non-invasive probes in the
virucidal action could potentially be a result of the lipophilic hospital30 . Non-critical surfaces of medical instruments that
nature of isopropyl alcohol as compared to ethanol.31 The are reusable are also disinfected with alcohol. Another advan-
efficacy of alcohols to inactivate viruses is heavily depen- tage of using alcohol as a disinfectant is that it is user friendly.
dent on the surface properties of the microorganism. Iso- Alcohol solutions are non-staining, evaporates quickly, low
propyl alcohol, by nature lipophilic, interacts favorably with toxicity compared to other forms of disinfectant, and have a
enveloped viruses and disrupts their activity effectively. The mild acceptable odor. These characteristics are critical in the
envelope layer of viruses mainly comprises lipid bilayers, healthcare settings as it contributes to the efficiency and the
which causes the membrane to be sensitive to the chem- necessary sanitization in the system.
ical and physical conditions.35 Non-enveloped viruses are
generally known to be more resilient to disinfectants com-
pared to enveloped viruses, and this includes alcohols. Stud- 3.2 Surfactants
ies have been shown that both alcohols are potent virucidal
agents against enveloped viruses such as Hepatitis B virus34 , Surfactants are amphiphilic moieties possessing both
Herpes virus36 ,SARS-CoV,37 and human immunodeficiency hydrophilic and lipophilic segments41 and are further classi-
virus (HIV)38 , but not non-enveloped viruses such as Hepati- fied into cationic,42 anionic,43 non-ionic,44 and zwitterionic45
tis A virus34 and polio virus.39 surfactants. They are often the active ingredients found in
LIN ET AL. 5 of 26
household disinfectants and detergents and have been demon-

strated to be capable of inactivating viruses.46–48 Due to
their amphiphilic nature, their main mechanism of viral
disinfection is usually solvating and disrupting the lipid-
based envelope of the virus.46 Enveloped viruses such as the
family of coronaviruses, among which they include SARS-
CoV-1,49 MERS,50 and the new SARS-CoV-2 viruses,51
are thus susceptible to these surfactants. However, some of
the surfactants do not rely on solvating lipid envelopes to
inactivate viruses. Surfactants such as sodium lauryl sulfate
(SLS) possess strongly hydrophilic heads that readily target
the capsid proteins, unfolding, and extracting them before
gradually solubilizing lipid membranes.43
3.2.1 Cationic surfactants (Quaternary

Ammonium Compounds)
Quaternary ammonium compounds (QACs) form the main

F I G U R E 1 Chemical structures of (A) benzalkonium chloride,
bulk of the cationic surfactants52 and they mostly inacti-
(B) didecyldimethyl ammonium chloride, (C) alkyl dimethyl benzyl
vate viruses by solvating and disrupting lipid envelopes or
ammonium saccharinate, and (D) cetyl pyridinium chloride
membranes46,53 . They are characterized by the presence of a
cationic ammonium group which is the hydrophilic head.53
The ammonium group has four organic substituents such minimum effective concentration (MEC) at 5 min is mostly
as alkyl or heterocyclic groups forming the lipophilic tail double that of the MEC for a 10 min reaction.46 MEC is
and the charge is balanced by an anion such as a halide or defined as the lowest concentration of the biocide that reduced
sulfate.54 Some of the most common QACs found in house- the virus titer value by 99.99% or greater as compared to con-
hold disinfectants include benzalkonium chloride,42 dide- trol reactions.46 This suggests that effective disinfection uti-
cyldimethyl ammonium chloride,46 alkyl dimethyl benzyl lizing QACs is best achieved using warm water and longer
ammonium saccharinate,55 and cetyl pyridinium chloride56 reaction times.62
(Figure 1). In addition to the common QACs, a new generation An advantage of utilizing QAC-based disinfectants is their
of QACs has also been developed and they are referred to as relatively high tolerance toward the presence of contaminat-
twin-chain or dialkyl quaternaries, examples include didecyl ing organic matter; their ability to inactivate viruses is usu-
dimethyl ammonium bromide57 and dioctyl dimethyl ammo- ally not diminished by the presence of organic matter46,63 as
nium bromide.58 They claim to retain virucidal activity better seen in other common disinfectants such as alcohol and chlo-
in hard water and also in the presence of anionic residues.59 rine based disinfectants.46 Tsujimura et al. demonstrated that
QACs are attractive as they are relatively nontoxic, col- the virucidal effects of MBAT and DDA are unchanged by
orless, and odorless.60 They are well-known for inactivat- the addition of 5% fetal bovine serum (FBS) but the MEC
ing enveloped viruses but their virucidal activity depends on of BZK increased by four times when exposed to 5% FBS.46
concentration, duration of application, and temperature.42,61 However, in another study by Rabenau et al.,64 the authors
Tsujimura et al. evaluated the virucidal effect of three demonstrated that the virucidal effect of BZK based disinfec-
QACs, namely benzalkonium chloride, (BZK), mono; bis (tri- tants against SARS coronavirus is not significantly reduced by
methyl ammonium methylene chloride)-alkyl (C9–15 ) toluene the presence of albumin or sheep erythrocytes. The seemingly
(MBAT), and didecyldimethyl ammonium chloride (DDA).46 contrasting results might be attributed to the fact that BZK dis-
It is found that the QACs require warmer temperatures to infectant formulations tested by Rabenau et al. contain other
exhibit more significant virucidal properties.46,62 The QACs active ingredients like glutaraldehyde and didecyldimonium
at their highest recommended concentrations of 0.05% (w/v), chloride too.64
0.02% (w/v), and 0.02% (w/v), respectively, had no virucidal QACs are regarded as lipophilic and target enveloped
effect on enveloped equine herpesvirus type 1 after 10 min viruses by solvating their lipid-based envelope.17 However,
reaction time at 0◦ C.46 When the temperature is increased to non-enveloped viruses are mainly characterized as possessing
room temperature, the virucidal activity of the QACs is found a protein capsid which is hydrophilic,17 thus QACs may have
to be dependent upon duration of reaction.46 Reaction times lower affinity and also lower disinfectant ability toward these
shorter than 1 min produced no virucidal effect, while the viruses.17,43,65 It is possible that the cationic moiety interacts
6 of 26 LIN ET AL.
organic matter contamination.46 LAS is able to effectively

inactivate equine herpesvirus type 1 at 0◦ C when applied at
0.05% concentration for 10 min. The minimum effective con-
centration (MEC) is reduced by four times when the tempera-
ture is raised to room temperature for 10 min. However, when
the duration is shortened to 1 min, the MEC rose to >0.05%.
In addition, MEC value at room temperature and 10 min reac-
tion duration increased by two times in the presence of 5%
contaminating FBS.
Although the main mode of disinfection by surfactants
is usually via solvating the lipid envelopes of viruses,17
surfactants like sodium laureth sulfate (SLS) that possess
F I G U R E 2 Chemical structures of (A) sodium laureth sulfate, (B) strongly hydrophilic heads have a different disinfection mech-
N-lauroylsarcosine and (C) sodium linear alkylbenzene sulfonate anism as compared to a more hydrophobic surfactant like
N-lauroylsarcosine (LS).43 The interaction between SLS
with the protein capsid on the non-enveloped viruses and lead and viruses is dominated by ionic interactions instead of
to viral inactivation.22,43,65 Romanowski et al. investigated hydrophobic interactions.43 SLS thus solubilizes liposomal
the virucidal effectiveness of benzalkonium chloride (BZK) membranes at a slow rate but bind rapidly to the protein com-
against common human ocular types of adenovirus that are ponent of Ca2+ -ATPase membranes causing unfolding and
non-enveloped viruses.42 The results suggest that the effec- extraction of the proteins.43 The viral penetration into cells
tiveness of BZK varies with the virus and also concentration can be divided into three stages, the first being the initial
of BZK. At the highest tested concentration of 0.1% BZK, attachment of the virus to the cell surface heparin sulfate, fol-
five adenoviruses are inactivated with virus titers >3Log10 lowed by forming stable attachment to the heparin sulfate, and
units while the remaining two adenoviruses are insufficiently then fusion of the virus with the cell membrane leading to
inactivated with reduced titers >1Log10 units but <3Log10 penetration of the virus into the cell.43 Piret et al. report that
units. Lower concentrations of BZK exhibited compromised SLS and LS reduce viral infection of cells by interfering with
ability to inactivate the adenoviruses. In another study by different steps of the viral penetration process.43 Incubating
Wood and Payne, a formulation with a final BZK concen- enveloped herpes simplex virus with LS reduced the first stage
tration of 0.2% (w/v) is found to be effective against non- initial binding to cells while SLS functioned by disrupting the
enveloped human coxsackie virus after 1 min of exposure fusion process between the viral envelope and cell membrane.
but was ineffective toward inactivating other more resistant As LS reduces the initial binding of the virus to cells, the viru-
non-enveloped viruses like poliovirus and human adenovirus cidal effectiveness of LS requires the pre-incubation of the
under the same conditions.22 The same BZK formulation is virus with LS in order to prevent future viral binding to cells.
also found to inactivate only some of the enveloped virus The lack of a pre-incubation period significantly reduced the
like the herpes simplex virus but failed to inactivate other virucidal effectiveness of LS. On the other hand, as SLS does
enveloped viruses like human immunodeficiency virus and not reduce initial viral binding to cells, the virucidal effects of
human coronavirus after 1 min of exposure.22 This shows that SLS is less reliant upon pre-incubation of the virus with SLS.
the virucidal effects of QACs are highly dependent upon the Moreover, it is also shown that SLS can exhibit viral inactiva-
specific virus and the conditions of exposure to achieve virus tion effects on viruses already firmly attached to cells. Due to
inactivation needs to be tailored. the complementary mechanisms of disinfection, the authors
suggested synergistic combination of SLS and LS in a single
formulation. In addition, the authors also note that the pres-
3.2.2 Anionic surfactants ence of contaminating organic matter reduced the disinfectant
ability of both SLS and LS and consequently concentrations 5
Sodium laureth sulfate, n-lauroylsarcosine, and sodium linear and 2.5 times higher respectively are required to achieve viral
alkylbenzene sulfonate (Figure 2) are some common anionic inactivation.
surfactants present in detergent and personal-care products
such as soaps, shampoos, and toothpaste,66 and they have been
demonstrated to be effective disinfectants towards a range 3.2.3 Non-ionic and zwitterionic surfactants
of viruses.48,67 In the study by Tsujimura et al., the authors
demonstrated that the disinfection ability of sodium linear Non-ionic surfactants are commonly used as emulsifiers and
alkylbenzene sulfonate (LAS) against enveloped equine her- can be classified by the type of bonds between the hydropho-
pesvirus type 1 is dependent upon duration, temperature, and bic and hydrophilic segments.44,68,69 The connecting bonds
LIN ET AL. 7 of 26
Zwitterionic surfactants are molecules bearing both

cationic and anionic charges but with an overall neutral
charge.71 Their virucidal activity is less investigated but
they may possess interesting properties. Crawford et al.
demonstrated that a zwitterionic detergent, Empigen BB®,
an alkylbetaine based on a C12-C14 alcohol, is able to inacti-
vate influenza A and B but still retain the biological activity
of the surface haemagglutinin (HA) and neuraminidase
(NA) antigens.45 The authors proposed that the mechanism
of disinfection by the zwitterionic detergent is via viral
disruption instead of solubilizing the surface proteins as
cationic, anionic, and non-ionic surfactants do.45,72 This
special ability to inactivate viruses but retain the biological
activity of their surface antigens allows the zwitterionic
detergent to be utilized during the development of vaccines.45
3.3 Oxidizing agents
Disinfectants such as sodium hypochlorite, hydrogen perox-

ide, and peracetic acid utilize their oxidizing capability to
inactivate viruses. For the small non-enveloped viruses such
F I G U R E 3 Chemical structures of non-ionic surfactants. (A) as noroviruses that are difficult to disinfect, strong oxidizing
Nonoxynol-9, (B) Triton X-100, (C) Brij-97 contain ether linkages. (D) agents are among the most effective disinfectants.73
Onyxol 345 contains amide linkage. (E) Span-20 and (F) Span-80
contain ester linkages. (G) Tween-20 and (H) Tween-80 contain
ether-ester linkages 3.3.1 Sodium hypochlorite
Sodium hypochlorite, the active ingredient in household

bleach, is a strong oxidizing agent. It dissolves in water to
are commonly amide, ether, ether–ester, or ester bonds.44,69,70 form hypochlorous acid, which can be reduced to form water
Nonoxynol-9 (nonylphenoxypolyethoxyethanol), Triton X- and the chloride anion. The hypochlorous acid molecule can
100 (p-diisobutylphenoxy polyethoxyethanol), and Brij-97 react with peptide bonds and thiol groups, chemically oxidiz-
(polyoxyethylene (10) oleyl ether) are non-ionic surfac- ing proteins and other biomolecules and abolish function.74
tants containing ether bonds (Figure 3A–C) while Onyxol The efficacy of disinfection decreases with an increase in pH,
345 (N,N-bis(2-hydroxyethyl)dodecanamide) contains likely due to the decreased proportion of hypochlorous acid
amide linkages44,70 (Figure 3D). Examples of non-ionic group present.75
surfactants containing ester bonds are such as Span-20 Sodium hypochlorite is fast acting, and is effective at
(sorbitan monolaurate) and Span-80 (sorbitan monooleate)44 low concentrations. At 10 ppm available chlorine, sodium
(Figure 3E,F). Lastly, Tween-20 (polysorbate-20) and hypochlorite is able to inactivate bacteriophage PAO1 within
Tween-80 (polysorbate-80) are non-ionic surfactants contain- 30 s, and further characterization studies showed that a large
ing ether–ester linkages44 (Figure 3G,H). These non-ionic number of structural components were damaged or deformed
surfactants inactivate viruses by solvating the viral envelope by the treatment. Generally, it was found that the extent
and disrupting the nucleocapsid.44 Their viral disinfectant of damage was proportional to the concentration of sodium
ability is highly associated with the type of linkages between hypochlorite and the contact time.24 Sodium hypochlorite at
their hydrophobic and hydrophilic segments.44 Non-ionic 0.5% (5000 ppm) could inactivate Ebola surrogate bacterio-
surfactants with ether and amide linkages have high virucidal phage Phi6 with 10 min contact time on a stainless steel sur-
effectiveness while those containing ester and ether–ester face, but not a nitrile surface.28 Sodium hypochlorite was able
linkages are much weaker at inactivating viruses when tested to inactivate adenovirus together with 5% serum at a concen-
under the same conditions.44 However, the high virucidal tration of 1900 ppm with 1 min contact time, achieving a mean
activity of the ether and amide containing non-ionic surfac- log10 reduction of infectivity of 4.87.76
tants also corresponded to high cytotoxicity and would thus Sodium hypochlorite can be used for difficult to disin-
require high dilution factors.44 fect non-enveloped viruses such as noroviruses. Sodium
8 of 26 LIN ET AL.
hypochlorite could inactivate Norwalk virus, a type of at 50 ppm was found to disinfect HIV in saline alone, but a
norovirus, at a concentration of 160 ppm after 30 s exposure, 50-fold higher concentration of 2500 ppm was required to
as quantified by RT-PCR.77 Sodium hypochlorite could also disinfect in the presence of 10% plasma, and 5,000 ppm
inactivate the norovirus surrogates, feline calicivirus and (0.5%) was required in the presence of blood.83 Sodium
murine norovirus, to greater than a 5 log10 reduction of dichloroisocyanurate at 10,000 ppm shows disinfectant activ-
infectivity with a concentration of 2700 ppm and 1 min.78 ity in the presence of 70% serum, while sodium hypochlorite
Sodium hypochlorite at 0.5% concentration with 1 min only shows similar activity in presence of 20% serum.85 This
contact time was able to deactivate the Hepatitis A virus, is postulated to be because only 50% of the total chlorine is
while another oxidizing agent peracetic acid was unable in the available hypochlorite/hypochlorous acid component
to do so.79 form that can be neutralized by serum, while the rest of
Sodium hypochlorite at high concentrations of 1000 ppm the chlorine can be progressively pushed toward hypochlo-
is regularly used for clinical disinfection. However, it has rite/hypochlorous acid to maintain the chemical equilibrium.
an odor and can be irritating to mucous membranes at high
concentrations. Less concentrated hypochlorous acid solu-
tions are less stable to environmental factors such as temper- 3.3.3 Hydrogen peroxide
ature and light, and the oxidizing potential can be used up by
impurities.80 In terms of application, a concentrated stock of Hydrogen peroxide is a strong broad spectrum inactivation
5% sodium hypochlorite that is more stable is typically rec- agent. It decomposes to form water, oxygen and the highly
ommended to be diluted 100× to 0.05% before use so as to reactive hydroxyl free radicals, which can cleave or crosslink
mostly avoid the downsides of concentrated sodium hypochlo- a large range of biomolecules including proteins, nucleic acids
rite during the disinfection process. The most common oxidiz- and lipids.17 A 13% solution with a 5 min contact time was
ing agent disinfectant in the United States is aqueous solutions able to inactivate to greater than 5 log10 reduction both the
of 5.25–6.15% sodium hypochlorite, also known as household enveloped virus Herpes Simplex virus, and the non-enveloped
bleach.81 virus poliovirus, showing a similar broad spectrum virucidal
Sodium hypochlorite is sensitive to the presence of organic activity.86 . An accelerated hydrogen peroxide-based (AHP)
material, and a significantly higher concentration is required disinfectant at a concentration of 0.5% and a contact time of
to achieve the same disinfectant efficacy. While 100 ppm 1 min showed a log10 reduction in infectivity of over 4 for
sodium hypochlorite can effectively disinfect a clean surface both enveloped and non-enveloped viruses, including HIV,
of HIV-1 virus in 30 s, the activity is reduced in the presence coronavirus 229E, poliovirus, and rotavirus (Wa).87 The AHP
of organic material. A higher concentration of 500 ppm and solution at concentration 0.5% was tested with another set of
1–2 min is required in the presence of 80% serum, and around enveloped and non-enveloped viruses, and showed effective
10,000 ppm (1%) is required in the presence of 80% blood.82 inactivation of the enveloped Sindbis virus and non-enveloped
Sodium hypochlorite at 50 ppm was found to disinfect reovirus within 5 min.88
HIV in saline alone, but a 50-fold higher concentration of Hydrogen peroxide was also effective against noroviruses,
2,500 ppm was required to disinfect in the presence of 10% although at generally higher concentrations than sodium
plasma, and 5,000 ppm (1%) was required in the presence hypochlorite. At a concentration of 0.18% and 5 min contact
of blood.83 In a review guidance for clinicians, noncritical time, the AHP disinfectant was able to inactivate feline
surfaces that are contaminated with blood or other tissues calicivirus, and at 3.5% and 10 min contact time, the AHP
are suggested to be cleaned first to remove organic material disinfectant was able to inactivate surrogate murine norovirus
before spot decontaminating with sodium hypochlorite to greater than 5log10 reduction.78 A 2.1% liquid hydrogen
solution.84 peroxide solution with 10 min exposure could inactivate
murine norovirus and bacteriophage Phi X174 on stainless
steel surfaces by 4 log10 units.89 A disinfectant comprising
3.3.2 Sodium dichloroisocyanurate of hydrogen peroxide and peracetic acid could inactivate
surrogate feline Calicivirus by 99.9% at an effective peroxide
Compared to sodium hypochlorite, sodium dichloroisocyanu- concentration of 0.1% and 15 min contact time.90
rate has disinfectant activity that persists for longer, is more Even when reused, a 7 % solution with a contact time of
tolerant to the presence of organic material, and has a higher 5 min was able to show an almost 5 log10 reduction in infec-
disinfectant efficacy overall. Sodium dichloroisocyanurate tivity of poliovirus, showing that some disinfectant activity
could inactivate the bacteriophage Phi6, an Ebola surro- was still present.91 A sonicated hydrogen peroxide system
gate, at 0.5% concentration in 10 min on multiple different with a cartridge containing hydrogen peroxide at 31.5% and
surfaces, while sodium hypochlorite could not inactivate 2 min contact time showed that it could attain a mean log10
sufficiently on nitrile surface.28 Sodium dichloroisocyanurate reduction of 5.20 for human papillomavirus (HPV).92
LIN ET AL. 9 of 26
F I G U R E 4 Chemical structures of (A) Sodium hypochlorite (B)

Sodium dichloroisocyanurate (C) Hydrogen peroxide (D) Peracetic acid
3.4 Peracetic acid
Peracetic acid decomposes in an analogous manner to form

the highly reactive hydroxyl free radicals, as well as acetic
acid and oxygen.93 Peracetic acid at 0.2% could inactivate
adenovirus 8 in hard water in 5 min, with a mean log10 reduc-
tion of infectivity of 4.75.76 Peracetic acid at 0.23% and at
a contact time of 15 min could reduce the infectivity of col-
iphage MS2 by greater than 3 log10 units. There was much
more effective deactivation as compared to hydrogen perox-
ide tested under the same setup.94 Peracetic acid at a low con-
centration of 85 ppm (0.0085%) and contact time of 1 min
could reduce the infectivity of a murine norovirus surrogate
by 3 log10 units in suspension, and reduced virus infectiv-
ity on surfaces of fruits and vegetables by 4 log10 units.73 F I G U R E 5 Chemical structures of (A) povidone-iodine;110 (B)
A peracetic acid and hydrogen peroxide-based disinfectant, chlorhexidine digluconate and (C) chloroxylenol
at an effective peroxide concentration of 0.1% and contact
time of 15 min could reduce infectivity of feline calicivirus, a
norovirus surrogate, by 4 log10 units in the absence of feces, virucidal properties for prolonged periods while decreasing
while a higher concentration of 2% was required in the “field- toxicity. Povidone-iodine is a broad-spectrum virucidal agent
like conditions” with feces as organic material impurity.90 manufactured in formulations containing 7.5-10% iodophor
Powder forms of peracetic acid at 0.5% concentration and 15 in solution, and are used in clinical applications such as ster-
min contact time could reduce the infectivity of porcine epi- ilizing agents for pre- and post-operation skin cleaning, in
demic diarrhea virus by more than 99.99% (4 log10 units).95 surgical swabs, scrubs and ointments, as well as everyday
These forms of peracetic acid were developed to provide products including antiseptic handwashes, mouthwashes and
higher stability and which could be dissolved in situ to form gargles that contain lower concentrations of the iodophor.98
the disinfectant solution. Povidone-iodine is not suitable for use with silicone prod-
ucts such as silicone catheters as iodine can cause accelerated
deterioration of the material.99 The iodophor is capable of
3.5 Halogenated compounds inactivating (≥ 4.0 reduction of log10 viral infectivity) a large
range of viruses which include the enveloped coronaviruses,
3.5.1 Povidone iodine influenza A100 and vaccinia virus, as well as non-enveloped
polyomavirus and adenovirus101 within 1 minute (Table 3).
Povidone iodine is an example of an iodophor, which For the most-resistant non-enveloped polioviruses however,
is a mixture of elemental iodine and a carrier polymer- aqueous formulations of povidone-iodine (Betaisodona ®
polyvinylpyrrolidone in this case. The carrier polymer has solution, containing 11% available iodine), required at least
no virucidal activity on its own.96 Iodine, the active and an hour for reduction of infectivity of ≥ 4.0log10 units.
powerfully-virucidal agent, exists as a complex mixture of In contrast, alcohol-containing povidone-iodine formulations
many species (e.g. I2 , I− , I3 − , IO− , IO3 − ) at equilibrium (e.g., Betaseptic Mundipharma®, containing 10% available
in water, but aqueous iodine solutions can be cytotoxic and iodine and ca. 40% 2-propanol and 40% ethanol) could inac-
cause irritancy.97 Hence, the polyvinylpyrrolidone polymer tivate these polioviruses within 5 min,101 owing to the syn-
entraps the various iodine-containing species by hydrogen ergistic virucidal activity of the iodophor and the alcohols.
bonding (Figure 5A), providing a reservoir of iodine for its Although it is generally safe and more effective in inactivating
sustained release in small doses at a time, maintaining its viruses than many other antiseptic agents (e.g., benzalkonium
10 of 26
TABLE 3 Comparison/summary table for virus review in suspension tests without organic load
Reduction of
*
activity (log10 ) OR
Concen- Reduction of virus Tempe-
tration Exposure titer (%) OR rature
Class Sanitizing agent Safety Application settings Advantages/Disadvantages (%) Virus time PFU/ml× (o C) Ref
Alcohols Ethyl alcohol Safe, non-irritant Hospital and home Pros: broad-spectrum and 70.0 Poliovirus (Sabin 1an) 1 min 0.4 37 39]
settings, personal non-staining 137

70.0 Murine Norovirus (CW3) 1 min >3.6 -
hygiene Cons: flammable, requires
specific concentration range to 70.0 Murine Norovirus (CW3) 5 min >3.6 - 137
be effective
70.0 Feline Calicivirus (F9) 1 min 0.5±0.6 - 137
70.0 Feline Calicivirus (F9) 5 min 2.6±0.3 - 137
70.0 Human immunodeficient virus 1 min >5.50 R.T. 138
(HIV) - I
70.0 Influenza A (H1N1) 1 min ≥4.84 20 139
60.0 Vaccinia virus strain Lister 1 min ≥4.38 ± 0.37 20 - 22 140
Elstree (ATCC VR-1549)
60.0 Modified vaccinia Ankara strain 1 min ≥5.40 ± 0.36 20 - 22 140
70.0 Mouse hepatitis virus (MHV) - 3.92 - 40
70.0 Transmissible gastroenteritis - 3.19 - 40
virus (TGEV)
Isopropyl alcohol Safe, non-irritant Hospital and home Pros: broad-spectrum and 70.0 Murine Norovirus (CW3) 1 min 2.6±0.3 R.T. 137
settings, personal non-staining 137

70.0 Murine Norovirus (CW3) 5 min >2.6 R.T.
hygiene Cons: only inactivates lipid
viruses, flammable, requires 70.0 Feline Calicivirus (F9) 1 min 0.1±0.1 R.T. 137
specific concentration range to

70.0 Feline Calicivirus (F9) 5 min 0.2±0.2 R.T. 137
be effective,
60.0 Vaccinia virus strain Lister 1 min ≥4.38 ± 0.37 20 - 22 140
Elstree (ATCC VR-1549)
60.0 Modified vaccinia Ankara strain 1 min ≥5.40 ± 0.36 20 - 22 140
(Continues)
LIN ET AL.
LIN ET AL.
TABLE 3 (Continued)
Reduction of
*
Cationic Surfactants Benzalkonium chloride Generally safe Hospital, industrial, Odorless, colorless, and 0.2 Human Adenovirus 1 min 0.25 R.T. 22
– Quaternary household non-caustic. Requires warmer 22

0.2 Herpes Simplex virus 1 min >4.51 R.T.
Ammonium disinfectants temperatures and longer
Compounds reaction time. Virucidal activity 0.2 Human Immunodeficiency Virus 1 min >1.87 R.T. 22
reduced by the presence of Type 1

contaminating organic matter.
0.2 Poliovirus 1 min 0.12 R.T. 22
0.2 Human Coxsackie virus 1 min >5.12 R.T. 22
0.2 Human Coronavirus 1 min 0.0 R.T. 22
0.2 Human Coronavirus ATCC 10 min 0.0 R.T. 22
VR-759 (Strain OC43)
0.05 Murine Hepatitis Virus (Strains 10 min >3.7 23 9
MHV-2 and MHV-N)
0.05 Canine coronavirus (Strain 1–71) 10 min >3.7 23 9
>0.05 Equine herpesvirus type 1 10 min 99% 23 - 25 44a
0.1 Human Adenovirus Type 3 1h 5.02 ± 1.57 33 42
(Isolate MC)
(Isolate MA)
0.1 Human Adenovirus Type 7a 1h 3.71 ± 1.87 33 42
(Isolate ED)
(Isolate CR)
0.1 Human Adenovirus Type 19/64 1h 3.66 ± 1.46 33 42
0.025 Equine herpesvirus type 1 1h 99% 23 - 25 44a
0.0125 Equine herpesvirus type 1 10 min 99% 23 - 25 44a
0.00175 Canine coronavirus (Strain S378) 3 days 3.0 37 9
(Continues)
11 of 26
TABLE 3 (Continued)
Reduction of
*
12 of 26
Didecyldimethyl Generally safe Hospital, industrial, Odorless, colorless, and 0.0025 Canine coronavirus (Strain S378) 3 days >4.0 37 9
ammonium chloride household non-caustic. Requires warmer 46

0.01 Equine herpesvirus type 1 10 min > 99.99% 23 - 25
disinfectants temperatures and longer
reaction time. Virucidal effects 0.02 Equine herpesvirus type 1 5 min > 99.99% 23 - 25 46
unaffected by organic load.

>0.02 Equine herpesvirus type 1 10 min > 99.99% 0 46
Mono; bis (tri-methyl Generally safe Hospital, industrial, Odorless, colorless, and 0.02 Equine herpesvirus type 1 10 min > 99.99% 23 - 25 46
ammonium methylene household non-caustic. Requires warmer

chloride)-alkyl (C9-15 ) disinfectants temperatures and longer
toluene reaction time. Virucidal effects
unaffected by organic load. >0.02 Equine herpesvirus type 1 10 min > 99.99% 0 46
Anionic Surfactants Sodium linear Generally safe Usually used as a Low cost. Virucidal effects 0.0125 Equine herpesvirus type 1 10 min >99.99% 23 - 25 46
alkylbenzene sulfonate foaming agent in reduced by organic load. 46

0.025 Equine herpesvirus type 1 5 min >99.99% 23 - 25
kitchen detergents Sensitive to water hardness.
for routine >0.05 Equine herpesvirus type 1 1 min >99.99% 23 - 25 46
cleaning
0.05 Equine herpesvirus type 1 10min >99.99% 0 46
Non-ionic Nonylphenoxy- High cytotoxicity Mostly used as High cytotoxicity and 0.01 Herpes Simplex Viruses - 1 1 min <500× 37 44
Surfactants polyethoxy ethanol emulsifiers spermicidal, dilutions by >500 44

0.01 Herpes Simplex Viruses - 2 1 min <500× 37
(Nonoxynol-9) times required
p- diisobutylphenoxy- High cytotoxicity Mostly used as High cytotoxicity and 0.002 Herpes Simplex Viruses - 1 1 min <500× 37 44
polyethoxy ethanol emulsifiers spermicidal, dilutions by >500 44

0.002 Herpes Simplex Viruses - 2 1 min <500× 37
(Triton X-100) times required
Sorbitan monolaurate Lower cytotoxicity Mostly used as Lower cytotoxicity, formulation 1 Herpes Simplex Viruses - 1 1 min 8.8*106 × 37 44
(Span-20) as compared to emulsifiers can be used without dilution

amide or ester
bearing
non-ionic 1 Herpes Simplex Viruses - 2 1 min 6.1*105 × 37 44
surfactants 44
Polysorbate-20 Lower cytotoxicity Mostly used as Lower cytotoxicity, formulation 1 Herpes Simplex Viruses - 1 1 min 4.3*106 × 37
(Tween-20) as compared to emulsifiers can be used without dilution
amide or ester
bearing
non-ionic
1 Herpes Simplex Viruses - 2 1 min 5.4*105 × 37 44
surfactants
Halogenated Povidone-iodine Generally safe, Hospitals, Long-lasting slow release of 0.23 Influenza A subtype H1N1 15 s 5.67 ± 0.43 20.0 141
compounds long-term disinfecting iodine, fast acting, more 141

0.023 Influenza A subtype H1N1 15 s 4.50 ± 0.54 20.0
exposure can handwashes, oral effective than many other
affect thyroid washes disinfectants. 0.23 SARS-CoV 15 s 4.60 ± 0.80 20.0 141
function and
0.23 MERS-CoV 15 s 4.40 ± 0.79 20.0 141
0.23 Rotavirus strain Wa 15 s ≥ 4.67 ± 0.42 20.0 141
8 Vaccinia strain Elstree Belgium 30 s ≥ 4.21 - 101
8 Adenovirus Type 5 3 min ≥ 4.63 - 101
8 Polyomavirus SV40 Strain 777 30 s ≥ 4.29 - 101
8 Poliovirus Type 1 60 min ≥ 4.93 - 101

LIN ET AL.
(Continues)
LIN ET AL.
TABLE 3 (Continued)
Reduction of
*
Chlorohexidine Low skin Handwashes, Ineffective against non-enveloped 0.02 Murine hepatitis virus 10 min 0.7 – 0.8 23 143
digluconate irritability, safe, mouthwashes and viruses. Less potent and 108
0.12 Herpes-simplex virus Type 1 30 s 97 % A.T.
good skin oral gels, slower-acting than
persistence disinfectants in povidone-iodine 0.12 Cytomegalovirus strain AD169 30 s > 99.7 % A.T. 108
hospitals142
0.12 Influenza A 1 min > 98 % A.T. 108
0.12 Parainfluenza Type 3 15 min 99 % A.T. 108
0.12 Hepatitis B virus 15 min 99 % A.T. 108
Chloroxylenol Generally safe Household Can cause skin irritation, highly 0.24 Herpes-simplex virus Type 1 1 min > 4.60 20 22
disinfectants, toxic to aquatic organisms

cleaning of
hospital surgical
equipment 0.24 HIV-1 1 min > 2.37 20 22
Aldehydes Formaldehyde Carcinogenic and Preservative, Pros: wide-spectrum activity 0.7 Murine hepatitis virus 10 min > 3.45 23 143
irritant. Needs hostpital Cons: Pungent, hazardous to 144

0.7 SARS-CoV isolate FFM-1 2 min ≥ 3.0 A.T.
to be used in a disinfecting agent health
well-ventilated 1.0 SARS-CoV isolate FFM-1 2 min ≥ 3.0 A.T. 144
area.
2.0 Vaccinia virus (ATTC VR-1536) 2h 4.9 4 114
4.0 Vaccinia virus (ATTC VR-1536) 3h 8.2 25 114
2.0 Human adenovirus Type 5 1h > 5.0 25 114
Glutaraldehyde irritant. Needs to Clinical settings Pros: broad spectrum 0.5 SARS-CoV isolate FFM-1 2 min > 5.0 A.T. 144
be used in a only, not suitable Cons: hazardous to health, 124

0.1 Poliovirus Type 1 30 min > 3.0 25
well-ventilated for household deactivates by polymerization
area. disinfection in alkaline media with time 0.1 Poliovirus Type 1 40 min 4.0 25 124
0.05 Poliovirus Type 1 60 min 3.0 25 124
0.02 Hepatitis A strain CF53 30 min 3.0 23 123
0.1 Echovirus Type 25 JV-4 5 min > 2.0 25 145
Oxidising Sodium hypochlorite Non-flammable. Cleaning and Pros: Broad spectrum, no toxic 0.01 HIV-1 30s 3.75 20 82
compounds Irritation to disinfection in residues, fast-acting 77

0.016 Norwalk virus 30s 5.0 -
mucous hospitals, Cons: Corrosive to metals at high
membranes at removing blood concentrations, Decreased 0.005 HIV-1 2 min ∼3-4 25 83
high stain activity in the presence of

0.005 Murine norovirus 3 1 min ∼2 - 73
concentrations. contamination organic matter
Low incidence 0.001 PA01 bacteriophage F116 30s >4.0 25 24
of serious
toxicity. (Continues)
Toxic chlorine gas
produced when
13 of 26
mixed with acid

14 of 26 LIN ET AL.
chloride, chlorhexidine digluconate),102 povidone-iodine may

cause thyroid dysfunction with long-term prolonged use,103
Ref
83
90
73
as well as allergic contact dermatitis,104 necessitating careful
medical monitoring.
Reduction of virus Tempe-
rature
(o C)
The origins of the broad virucidal efficiencies of povidone-
25
20
-
iodine has still yet to be fully elucidated, and is likely to occur
by multiple mechanisms, reducing the likelihood of chance

*
Reduction of
titer (%) OR
viral mutations conferring resistance. There is evidence that

PFU/ml×
iodine can block the receptors of the virus responsible for

∼3-4
attachment to the host cell surface.100 Furthermore, iodine

>3
∼3
can inhibit the activity of viral enzymes (e.g. neuraminidase)
Exposure
essential for virus release from host cells, preventing its spread
15 min
2 min
1 min
to other uninfected cells.98 For enveloped viruses, it has also
time
been suggested that virus membrane can be destabilized by

Feline calicivirus F9 (norovirus)
the reaction of iodine with the unsaturated C=C bonds of

membrane fatty acids.105
Murine norovirus 3
3.5.2 Chlorhexidine digluconate

HIV-1
Virus
Chlorhexidine is a broad-spectrum cationic bisguanide bio-

cide (Figure 5B) found in many antiseptic products. An
Concen-
active ingredient in handwashes, mouthwashes and oral gels

tration
0.0085
Pros: Broad-spectrum, fast-acting, 0.005
(%)
0.1
(e.g., Corsodyl®), disinfectants, and preservatives, chlorhex-

idine has generally low irritability, good substantivity on
Cons: corrodes metals, unstable
skin, and rapid bactericidal activity. However, its activity

presence of organic matter,
long shelf life, easy to ship
Pros: Broad-spectrum, stable

Application settings Advantages/Disadvantages
decrease in activity in the
Pros: Fast acting, leaves no

residue, still effective in
Cons: Strong smell, Some
is highly dependent on its formulation, being reduced by

the presence of organic matter, including serum, as well as
Cons: Slower acting
organic matter
anionic surfactants and phospholipids106 as well as being

pH-dependent.17 Compared to bacteria, its virucidal activ-
ity is more variable and significantly less effective and
slower-acting than povidone-iodine. Generally, chlorhexi-
dine is ineffective against non-enveloped viruses (polio and
Disinfecting medical
adenoviruses), but shows variable potency for inactivat-

equipment
ing enveloped viruses (e.g. herpes simplex virus, Influenza

Abbreviations: AT, unspecified ambient temperature; RT, room temperature.
A, cytomegaloviruses and hepatitis B virus) (Table 3).

Against human coronavirus HCoV-299E however, chlorhex-
-
∗ Values given as log reduction factors unless otherwise specified.
idine showed limited effectiveness, with a 1.0 mM solution

inflammation due
to insufficient
showing only a 3 log10 reduction after 1 hour.107 Mecha-

nistically, the viral inhibition of chlorhexidine has been pro-
rinsing
Safety
posed to arise from interactions with surface glycoproteins

-
on enveloped viruses, which may reduce the activity of viral

enzymes such as DNA polymerase enzymes for the hepati-
dichloroisocyanurate
tis B virus.108 This chlorhexidine-receptor binding is sug-

Hydrogen peroxide
Sanitizing agent
gested to account for its effectiveness, albeit slow, against

Peracetic acid
rotaviruses,109 which are non-enveloped viruses containing

(Continued)
Sodium
surface glycoproteins that allow host cell infection.

10
3.5.3 Chloroxylenol
TABLE 3
Class
Chloroxylenol, also known as para-chloro-meta-xylenol

(PCMX) (Figure 5C), is a halogenated phenolic-type
LIN ET AL. 15 of 26
thus it is not used as a household disinfectant. Formalde-

hyde has been shown to be a slower-acting disinfectant than
glutaraldehyde.17
F I G U R E 6 Chemical structures of (A) formaldehyde (B) 3.6.2 Glutaraldehyde

glutaraldehyde and (C) ortho-phthalaldehyde
Like formaldehyde, glutaraldehyde (or sometimes known as
glutardialdehyde) (Figure 6B), is a powerful broad-spectrum
antiseptic used as the key active ingredient in Dettol®. disinfecting and sterilising agent which is highly effective
Commonly-used for household disinfectants, wound clean- against many viruses after short exposure times (Table 3).
ing, and for disinfecting surgical equipment, it is most This dialdehyde is usually sold as an acidic solution, but
effective against bacteria, but its virucidal activity is variable. its reactivity can be “switched on” by making the solution
A 1998 study of chloroxylenol against a number of human alkaline at pH > 7.5. In an alkaline solution, glutaralde-
viruses found it to be effective against the enveloped viruses hyde has a limited shelf-life and stability, as its tendency to
herpes simplex 1 and HIV (Table 3), but was practically polymerise120 can reduce the number of reactive available
ineffective against the non-enveloped polioviruses, ade- free aldehyde groups essential for its virucidal activity. To
noviruses and coxsackie virus, as well as the enveloped determine the reactivity of glutaraldehyde solutions, chemical
human coronavirus ATCC VR-759.22 However, a later tests have been developed, though the manufacturer’s instruc-
study using the murine hepatitis virus as a surrogate for the tions must be carefully adhered to for accurate results to be
SARS coronavirus found it to be highly effective (≥4.50 obtained.121 In a similar manner as formaldehyde, the alde-
log10 reduction) within a 30 s contact time.111 In spite of its hyde linkages of glutaraldehyde can react with the reactive
widespread commercial use for a long time, surprisingly little groups on proteins, RNA and DNA. However, as a dialdehyde,
is known about its mechanism of action against both bacteria its two reactive functional groups can form inter- and intra-
and viruses. Chloroxylenol is generally safe to humans for molecular crosslinks with these biomolecules that destroys
external use, but has been reported to cause irritant contact their activity.122 For instance, glutaraldehyde inactivates the
dermatitis and contact depigmentation.112 hepatitis A virus and enteroviruses by reacting with lysine
residues on their surfaces.123 Reactions with capsid proteins
are also proposed to account for its virucidal effectiveness
3.6 Aldehydes against polioviruses.124,125
Glutaraldehyde solution (2.0%) is usually used to decon-
3.6.1 Formaldehyde taminate surgical equipment, endoscopes, and dialyzers in
clinical settings, but it needs to be used in a well-ventilated
Formaldehyde is the simplest aldehyde (Figure 6A) and a setting by trained personnel due to its strong and unpleasant
powerful high-level disinfectant with potent viral inactiva- odour. Although not suspected to be carcinogenic,126 it is
tion capabilities. Often sold as an aqueous solution called known to cause dermatitis and irritation to mucous mem-
formalin, it has been used to inactivate viruses for vaccine branes in eyes, nose, and mouth.127 Due to these reasons, it
production113 and for scientific study114 As a high-level disin- is not used as a household disinfectant. Generally, metals,
fectant, it can effectively and quickly inactivate many different rubber, plastics, and lensed instruments are tolerant to
types of viruses (Table 3) both in suspension and on surfaces, glutaraldehyde, though it has been recommended not to be
by chemically alkylating the amino (NH2 ) and sulfhydryl used to disinfect non-critical surfaces due to its cost.128
(SH) groups of proteins,115 as well as the amino groups of
nucleic acid bases (e.g. adenine) of DNA and RNA.116 As
these functional groups are more reactive at alkaline pHs 3.6.3 Ortho-phthalaldehyde (OPA)
than acidic pH, formaldehyde is most effective as an alka-
line solution. However, its high reactivity renders its usage Ortho-phthalaldehyde, or 1,2-dicarboxybenzaldehyde
health-hazardous: other than being a mutagen and suspected (Figure 6C), is another high-level disinfectant. Like both
carcinogen,117 it causes irritation of exposed body surfaces formaldehyde and glutaraldehyde, its virucidal properties
(e.g. skin and eyes).118,119 Furthermore, its pungent odour stem from its reactions to crosslink reactive groups of
can be detected at concentrations lower than 1 ppm. As a proteins and nucleic acids. Although it is a less potent
result, other than usage in a well-ventilated area, strict reg- crosslinking agent than glutaraldehyde, this deficit is made
ulations for human exposure govern its use as a disinfectant up for by its more lipophilic aromatic nature which enhances
and sterilizing agent in hospitals and healthcare facilities, and its uptake by the lipid membrane, and has even shown faster
16 of 26 LIN ET AL.
bactericidal activity than glutaraldehyde.129 While OPA’s During the course of pursuing these options, it is of high
bactericidal properties are well-documented,130 its efficacies imperative to consider the efficacies of these alternatives to
against viruses is less well established (Table 3). A study ensure that ineffective options do not lull consumers into a
in 2006 using stainless steel careers showed that a 0.55% false sense of security.
OPA solution could gave 4.84 log10 reduction in adenovirus
8 after 1 min exposure.131 0.3% and 0.5% OPA solutions
gave > 3 log10 reduction in the respective infectivities of 4.1 Essential Oils
surrogate hepatits B and C viruses on glass surfaces after a 1
min exposure.132 To assess the effectiveness of OPA against Commonly used in a variety of skincare products to treat der-
coronaviruses, a study using the surrogate mouse hepatitis matological issues such as acne, essential oils were known to
virus on stainless stell surfaces showed 1.7 log10 reduction in be both topically safe and able to combat a variety of skin-
infectivity after 1 min contact with 0.55% OPA.133 However, associated pathogens. Yet, their explored germicidal activi-
the same concentration of OPA was found to be ineffective ties are mostly bacteria-related, and hence cannot be directly
against a suspension of human papillomavirus type 16 after extrapolated into effective disinfection of all viruses.147
a 45 min incubation.134 There us a current dearth of studies In terms of research into the anti-viral or viral inhibiting
on the effectiveness of OPA against suspended viruses, and efficacies of common essential oils, several oils have been
more studies are required to establish the general virucidal proven effective against select viruses, such as the herpes
efficicacy of OPA against a wider variety of viruses. simplex virus type-1 or the bovine viral diarrhea virus.148
OPA has numerous advantages over glutaraldehyde. First, The operative mechanism of action, however, varies greatly
it is chemically stable between pH 3 and 9 and does not require between the different essential oils, and, depending on the
any further activation prior to usage. Second, it does not have stage of inactivation, render them effective against only cer-
a strong perceivable odour and does not irritate the skin, eyes, tain specific strains.149
or nasal mucosa.135 As a result, exposure monitoring is not Through the study of star anise oil and some essential oil
required for its usage, unlike glutaraldehyde. Furthermore, its constituents, for example, it was identified that the oil itself,
excellent material compatibility129 allows its usage as a disin- as well as the specific compounds trans-anethole, farnesol
fectant in many clinical settings such as for endoscopes135,136 and 𝛽-caryophyllene were capable of direct inactivation of
and urological instruments. However, OPA can stain exposed the herpes virus, potentially through the disruption of the
skin grey, and hence has to be rinsed off with copious quanti- virion envelope, prior to host cell infection.149 Other reports
ties of water, or used with personal protective equipment (e.g. indicate that anti-viral activities of essential oils do happen
gloves and eye protection). For this reason, it is not used as a through similar mechanisms, including the virucidal effects
common household disinfectant. of sesquiterpenes against various enveloped viruses,150 and
the inhibitive effects of eugenol against the herpes simplex
virus.151 Due to the lack of research investigating the spe-
4 M Y T H S A BOU T V I RU C I DA L cific virucidal actions of these compounds against the selected
AGENTS viruses, it is unsafe to assume that effective sanitization can
occur broadly over all recommended types of essential oils.
The practice of maintaining adequate personal hygiene and When considering several of the aforementioned cases as
environmental sanitation can be considered to be the single examples, most of which act upon the virion envelope, it is
most consistent strategy that has been employed throughout possible to conclude that they would be rendered ineffective
the evolution of healthcare methods in combating the vari- in the disinfection of non-enveloped virus species.
ous epidemics the world has faced.146 Advisories issued by At the same time, it is also important to note that their pur-
governmental agencies and the healthcare sectors alike have ported antiviral activities may not be directly relevant to the
stressed its importance, ingraining in the minds of a wide purposes of sanitization or disinfection. Antiviral activities
audience the need for the procurement of viable sanitizing such as the inhibition of viral replication or gene expressions,
agents. while potentially effective in the treatment of viral infections,
The global outbreaks of highly infectious viruses such as may not necessarily be what the user is expecting in terms of
the SARS-CoV-2 have thus understandably seen rises in the a topical or surface disinfectant.
mass purchasing of sanitizers and disinfectants, resulting in
the issues of maintaining adequate supplies around several
countries in the world. Without this option, a segment of the 4.2 Antibiotics
population has turned to the possibility of do-it-yourself for-
mulations or alternative products that, along with the rise of The development of global anti-microbial resistance due to
social media, have largely been proliferated on the internet. the over-prescription of antibiotics is indicative of their high
LIN ET AL. 17 of 26
exposure to the public community. This could potentially upon a reduction of UV intensity, the virucidal action of
allow for growth in public sentiment with regards to the belief UVGI can be compensated through the increase of exposure
that antibiotics are capable of treating a variety of diseases, time.161 When tested for four different strains of airborne
including those caused by various viruses. An early survey of bacteriophages: ssRNA (MS2, ATCC 15597-B1), ssDNA
the public in the Netherlands showed that almost half of the (ΦX-174, ATCC 13706-B1), dsRNA (phi 6 with envelope
population incorrectly believed in the ability of antibiotics in lipid, ATCC 21781-B1), and dsDNA (T7, ATCC 11303-B1),
treating infections caused by viruses. In the same study, 90.9% it was reported that the required UVGI dose required was
believed in the need for antibiotic treatment when faced with approximately increased twofold when attempting to increase
pneumonia, and another study in a different area reported a 90% inactivation to 99% inactivation.162 In the same study, it
94.2% of the population sharing this belief.152153 This set of was also observed that certain strains of viruses were more
patient beliefs could have a negative impact on the decisions vulnerable to UVGI than others. The UVGI doses required
of healthcare professionals due to the pressure of catering to were, in increasing order, 339–423 μWs/cm2 for ssRNA, 444–
patient demands, even though it was shown to have no effect 494 μWs/cm2 for ssDNA, 662–863 μWs/cm2 for dsRNA, and
on the patient recovery and satisfaction.154 910–1196 μWs/cm2 for dsDNA.162 A similar ranking was
In fact, statistical evidence has shown that the inappropri- reported when it came to observing the sensitivities of similar
ate use of antibiotics prescribed by medical professionals has virus classes on a surface medium (as opposed to aerosol).158
been observed to be high even up till recent years, where it was The susceptibility of viruses to this method was thought to be
estimated that up to 30% of antibiotic prescriptions among dependent on several factors, such as physical size, molecular
outpatients may have been inappropriate.155 This could have weight, DNA conformation, repair enzyme, and chromophore
potentially stemmed from a variety of reasons, including per- presence, clumping propensity, etc., which could all affect the
ceived patient expectation154 and misdiagnoses due to the UV dose required.163
similarities in the manifestations of clinical symptoms.156 As As such, while there is a high potential for UVGI to serve
such, the correction of patient beliefs is still fundamental in as a virucidal technique, and even solar radiation to play a
the prevention of antibiotic overuse in such clinical settings. major role in environmental virucidal activity under appro-
priate conditions,164 it is important to consider the set of cir-
cumstances under which these are true.
4.3 Ultraviolet germicidal irradiation (UVGI)
There has been a long history of the employment of ultraviolet 4.4 Vitamin C
light in the elimination of microbial pathogens, whereupon its
efficacy has been regarded highly enough for it to see use even A popular dietary supplement, Vitamin C has had a history of
in the disinfection in the laboratory and healthcare settings.157 being recommended in popular literature for the purposes of
It can thus be anticipated that there will be the resulting per- treating respiratory infections.165 While earlier studies have
petuation of the notion that UVGI will be an effective agent in demonstrated its ability to prevent and alleviate the symp-
the combating of viruses. While this belief does hold merit, it toms of virus-induced respiratory infections, its mechanism of
is important to examine the restrictive conditions under which action, as well as its virucidal potency, were not examined.165
this does hold true. Prior to this, Vitamin C was the subject of various stud-
First, as the efficacy of UVGI is dependent on the absorp- ies that investigated and concluded on its potential to inac-
tion by the target DNA, which has a maximum absorption tivate the poliomyelitis virus under in vivo settings, but the
wavelength of 260 nm, microorganisms have been found to route of its administration was either through injections166
be selectively vulnerable to the exposure to light at wave- or nasal instillation.167 It was however reported that, in this
lengths specifically at or in close range of 253.7 nm.158 When case, the dosage required was sufficiently low to be achieved
tested against the strain of bacteriophage virus ΦX-174, it via supplementation.168 Another in vivo study of viral inac-
was shown that the wavelength could be increased to up to tivation involving the herpes virus also was achieved via
280nm without significant reduction of virucidal efficiency, injection.169 Apart from these, various other studies involving
but a significant decrease was observed upon the increase to different virus strains, such as rabies170 and enteroviruses171 ,
301 nm.159 have reported in vitro viral inactivation.
Second, it has been shown that the germicidal activity of The sum of gathered literature so far suggests, however, that
UVGI is compliant with the Bunsen–Roscoe reciprocity law, the desired properties of ascorbic acid are achieved mainly
where it was established that the efficiency of inactivation is through a combination of its ability to inactivate the virus,
dependent on UV dose, which is the product of UV inten- inhibit intracellular virus replication, as well as the other ben-
sity (mW/cm2 ) and exposure time (seconds).160 The result- eficial effects of the vitamins, which in turn render it capa-
ing implications in the translation into application mean that, ble of alleviating the severity of a range of virus-related
18 of 26 LIN ET AL.
diseases.168 While indicative of the potential of the use of the hypertonic saline nebulization of children with respiratory
vitamin C to supplement medical therapy, this does not nec- syncytial virus bronchiolitis showed no significant alleviation
essarily imply its potency as a virucidal disinfecting agent. of their symptoms.176
The studies regarding saline solutions thus far, however,
have mostly been investigations into its clinical effects, which,
4.5 Garlic while somewhat suggestive of its potential in symptom reduc-
tion, are not sufficient to prove if it does possess virucidal
The basis of some of these myths stems from their com- behavior for disinfection purposes.
mon association with antimicrobial properties. Garlic is com-
monly associated with fairly broad-spectrum antimicrobial
effects, exhibiting antibacterial, antifungal, antiviral and even 5 NEW RESEARCH DIRECTIONS
antiprotozoal activities. Its constituents that render it effec- TOWARDS VIRUCIDA L AGENTS
tive against viruses have been discovered to include allicin, A N D M AT E R I A L S
diallyl trisulfide, and ajoene.172,173 It has displayed antivi-
ral effects against a variety of viruses, including influenza A To expand the repertoire of virucidal compounds available,
and B, rhinovirus, HIV, herpes simplex 2, cytomegalovirus, there has been considerable research effort to develop new
viral pneumonia, and rotavirus.174 In specifically consider- active materials which exhibit broad spectrum virucidal
ing its virucidal range, garlic has been shown to be effec- activities, yet pose low toxicities to humans. Three main
tive against herpes simplex virus type 1 and the parainfluenza types of virucidal agents are receiving significant research
virus type 3.173 The virucidal effects of garlic and its active attention: small discrete virucidal molecules (Section 5.1),
compounds do not cover the entire range of virus strains, and metal nanomaterials (Section 5.2), and virucidal polymers
they have been shown to be ineffective against certain types, (Section 5.3). There is a considerable push towards utilizing
such as the coxsackievirus.175 High concentrations of garlic naturally-occurring molecules to exploit their intrinsic
extract have also been shown to be toxic to cells, therefore cau- virucidal properties as much as possible. In this section,
tion is advised when garlic is attempted to be used.175 Thus, we will give a broad overview of emerging directions
prior to turning to garlic as a viable alternative to conventional towards virucidal agents and materials, which are not yet
disinfectants, it is imperative to consider the strain of microbes commercially available, and/or their virucidal properties are
to be eliminated, as well as whether garlic can be applied in a only demonstrated under controlled lab settings and not yet
safe yet effective manner. conclusively proven under real-life usage conditions.
4.6 Saline Solutions 5.1 New virucidal molecules
Apart from the aforementioned, there have also been various 𝛽-cyclodextrins (𝛽CDs) are naturally-occurring macrocyclic
other myths circulating in the online community with regards molecules comprising of 7 covalently-joined glucopyranose
to the prevention of the infections, especially with the case of units, possessing a hydrophilic exterior and a hydrophobic
the latest COVID-19 pandemic, leading to the need for the interior cavity which can encapsulate non-polar molecules
clarification that has been conducted by the WHO and the in water. A family of sulfonated 𝛽CDs was recently studied
official media of various countries. As mentioned in the pre- for their virucidal activities (Figure 7A), which differed in
vious segment, another commonly perpetuated belief is the the length of the flexible alkyl groups between the anionic
inability of rinsing of the nose with saline solution, or gar- sulfonate groups (CD1 and CD2), as well as rigidity of
gling with salt water, to treat viral infections. Possibly due to the spacer unit (CD3).177 CD1 displayed broad-spectrum
its location of action, this is commonly associated with the virucidal activity against many viruses from different fam-
treatment of upper respiratory tract infections and has a his- ilies, including from herpes simplex virus type 2 (HSV-2),
torical basis in the ancient practices from India.176 respiratory syncytial virus types A and B, human metap-
Upon investigation of its in vivo efficacy, it was shown neumovirus and human parainfluenza virus type A, while
that hypertonic saline nasal irrigation was capable of reduc- being ineffective against enterovirus D68 and influenza
ing the duration of illness by 22%, over the counter medicine virus H3N2. The long alkyl linker of CD1 appeared to
use by 36% and illness in household members by 35%. Thirty be the key to its high virucidal activity, giving complete
percent more individuals also saw a reduction in viral shed- HSV-2 inactivation within 15 minutes, and whose virucidal
ding by ≥0.5 log10 per day, which could serve as a reason activity was not affected by dilution. Compared to CD1, a
for the lowered transmission rates.176 The result shown, how- shorter linker in CD2 and a more rigid one in CD3 made the
ever, was not necessarily always positive, as some studies into cyclodextrin derivatives less effective. It was proposed that
LIN ET AL. 19 of 26
inactivate two norovirus surrogates completely at a concentra-

tion of only 0.5%.179 The grape seed extract was also shown to
reduce the hepatitis A virus and feline calicivirus on infected
lettuce and pepper after a minute of incubation180 . These edi-
ble food extracts could be potentially used as virucidal agents
in self-sanitizing food packaging applications.
5.2 Metal nanomaterials
Silver and its salts have had a long history of use as anti-
septics and disinfectants, and their broad-spectrum biocidal
properties are well established.181 Silver dihydrogen citrate,
for instance, can reduce the infectivity of feline calicivirus, a
surrogate for the human norovirus (which causes diarrhea and
vomiting), by > 4 log10 units after 1 and 30 min in suspension
and on glass surfaces, respectively.182 Silver nanoparticles
(AgNPs) are a class of silver nanomaterials and are defined
as dispersions of silver particles between 10 and 100 nm
in size. Generally, AgNPs are effective biocides in small
doses,183 although their potential toxicities to humans are still
under intense debate.184,185 Modern methods have enabled
AgNPs of well-defined shapes, particle sizes, and polydisper-
sity to be synthesized,186 which are important parameters that
F I G U R E 7 Structures of novel virucidal molecules: (A) dictate their eventual biocidal activities, biological fate and
𝛽-cyclodextrin alkyl sulfonates177 and (B) 1,3-bis(bithiazolyl)-
toxicity.187
tetra-para-sulfonato-calix[4]arene.107
The virucidal properties of AgNPs are still largely unex-
plored, but initial reports are encouraging. AgNPs can inhibit
CD1’s best virucidal activity against HSV-2 stemmed from viruses by a number of mechanisms, including binding to and
its ability to bind to most numbers of glycoprotein B found interacting with viral surface proteins,185 as well as denatur-
on the viral surface, blocking the proteins‘ fusion loop and ing enzymes by reacting with amino, carboxyl, imidazole,
induces conformational changes to these proteins. and sulfhydryl groups.188 In a study using 30–50 nm AgNPs
In addition to cyclodextrin derivatives, macrocyclic surface-coated with polyvinylpyrrolidone against various
calix[4]arene derivatives also showed promising viru- strains of HIV-1, the AgNPs were found to bind onto surface
cidal activities. 1,3-bis(bithiazolyl)-tetra-para-sulfonato- glycoproteins (gp120) and chemically modifies it by denatur-
calix[4]arene (C[4]S-BTZ) (Figure 7B) was shown to ing its disulfide-bonded domains.189 This prevents the virus
show better virucidal activities against human coronavirus from binding to receptor proteins on potential host cells which
HCoV-229E than the frequently used antiseptic, chlorhex- are necessary for viral entry and infection. Dilute AgNP solu-
idine (CHX) (Section 3.5).107 Firstly, C[4]S-BTZ were not tions could elicit significant virucidal activity, as inhibition
cytotoxic towards L-132 cells, whereas CHX and HXM of 50 % of viral infectivity could be attained at AgNP con-
showed notable toxicities with IC50 values of 4.3 × 10−6 centrations of ≤ 0.91 mg/mL. Compared to commonly-used
and 3.8 × 10−5 mol/L, respectively. In addition, C[4]S-BTZ biocidal silver nitrate and silver sulfadiazine, the AgNPs were
demonstrated a faster virucidal rate as compared to CHX107 . found to be more effective against the HIV-1 strains, suggest-
At a concentration of 10−3 mol/L, a 5 min-incubation of ing that the release of Ag0 atomic clusters from the AgNPs is
HcoV-229E with C[4]S-BTZ reduced viral titers by 2.7 log10 more potent virucide than Ag+ itself. Such destruction of viral
units, as compared to just 1.4 log10 reduction for the same surface glycoproteins has also been suggested to account for
concentration and duration of CHX. the virucidal effects of AgNPs against the Influenza virus.190
Interestingly, some compounds found in food were found AgNPs have also been incorporated into polymer films com-
to exhibit virucidal activities. Cinnamaldehyde, an organic prising of poly (3-hydroxybutyrate-co-3-hydroxyvalerate),
compound that is responsible for cinnamon’s flavor and a biopolymeric material, which achieved the dual function
odor, was effective against norovirus surrogates and hepati- of stabilizing the AgNPs and bringing about virucidal
tis A virus178 . Carvacrol, a natural monoterpene derivative of behavior against norovirus surrogates.191 AgNP-containing
cymene, also known as a natural food additive was found to products are appearing increasingly in the market, including
20 of 26 LIN ET AL.
5.3 Polymers for inactivating viruses
Polymers capable of inactivating viruses are a new and excit-

ing area of research. A large number of polymers capable of
killing bacteria and preventing their proliferation are known
today,196 but comparatively very few are known to be viru-
cidal. Such polymers can: (1) act as carriers for controlled
release of bioactive virucidal molecules, or (2) possess intrin-
sic viral inhibitory properties on their own due to the chemical
functional groups present on the polymer structure. Compared
to the former, whose virucidal efficiencies are limited by dif-
F I G U R E 8 Illustration of virus disinfection using the fusion and initial loadings of the bioactive agents through
self-disinfecting surface powered by visible light. Figure reproduced
the polymer matrix, the latter has the advantage of show-
from ref. 195 with permission from the Royal Society of Chemistry
ing long-term activity. Furthermore, these intrinsically viral-
inactivating polymers can be formulated or cast into various
forms for customized applications, such as disinfecting coat-
clothing, wound-dressings, ointments, and food packaging ings, binders in pharmaceutical products, water purification
materials,192 whose biocidal activities are a result of slow filters, and as additives in paper or common household mate-
sustained-release of the silver nanomaterials. However, it rials. For these reasons, we discuss only intrinsically-virucidal
should be noted that like all disinfecting agents aforemen- polymers here.
tioned, the virucidal efficacies of AgNPs differ from virus to The vast majority of viral-deactivating polymers are
virus. Furthermore, the quantities, shapes, size, and types of charged. In 2006, Klibanov reported that hydrophobic
silver nanomaterials released depend on their real-world set- polyethylenimine (PEI) derivatives can inactivate enveloped
tings and applications,193 all of which affects their virucidal viruses such as the Influenza A virus.197 Cationic and zwit-
properties. Thus, the effectiveness of these AgNP-containing terionic (possessing equal numbers of positive and negative
products against viruses in real-life settings, as well as their charges) PEI derivatives (Figure 9A) showed close to com-
toxicity towards humans, need to be carefully evaluated and plete the virucidal activity in 5 min. On the other hand, much
studied. slower virus inactivation was reported for anionic PEI, reach-
Other than AgNPs, gold nanoparticles (AuNPs) are also ing 89 % virucidal activity only after 2 hr, while the neutral
promising virucidal agents. AuNPs synthesized using garlic derivative showed no virus inactivation. Notably, an alcoholic
extract with an average size of 6 nm showed virucidal activ- solution of these polymers could be painted onto glass slides
ity against the measles virus by also binding to surface viral to form virucidal coatings. The inactivation was proposed to
receptors and preventing subsequent host cell binding and arise from the interaction of the erect charged polymer “tenta-
infection.194 However, due to the cost of the gold chemical cles” with ionic sites within the hydrophobic lipid membranes
precursors, AuNPs are unlikely to become cheap and com- of the Influenza A virus. A similar mechanism of action likely
mercially widely available disinfecting agents. accounted for the virucidal activity of cationic pyridinium-
The use of metal nanomaterials to form self-disinfecting type polyvinylpyrrolidones (Figure 9B), which damages the
surfaces have gained traction in recent years, as viruses can lipid envelop of Influenza A and leads to virostasis.198 Pyri-
persist on contaminated surfaces for prolonged periods. Self- dinium polymers with a high degree of chemical crosslinking
disinfecting surfaces are capable of inactivating viruses in which are insoluble in water are also effective in removing
contact with them in situ, reducing the chances of virus viruses from water.199
transmissions via human contact with contaminated surfaces. The lack of a lipid membrane in non-enveloped viruses
In one design, the self-disinfecting surface was established (e.g. adenoviruses) necessitates a different strategy for inacti-
with photoactive metal nanocrystals which required visible vation. The cationic quaternary phosphonium polymer in Fig-
light stimulation for viral inactivation. These surfaces, fab- ure 10 achieves this by interacting with the binding fiber pro-
ricated from nanocrystals of CuInZn4 S6 (CIZS) with band teins on the virus, preventing them from binding to cellular
gaps within the visible light range, could absorb visible receptors necessary for entry into cells. At aqueous concentra-
light and produce active oxidative species that inactivated tions as low as 100 ppm, these non-cytotoxic polymers have
the influenza A virus by oxidizing the amino acid residues a virucidal efficiency of 86.5%.200
presented on the viral envelope proteins (Figure 8). While In 2013, cationic chitosan derivatives (Figure 11) were
highly virucidal, visible light must be present to guarantee the shown to be highly potent for inhibiting the replication of
self-sanitizing effect, thereby limiting the practicality of the human coronavirus HCoV-NL63, a common cold virus.201
system. The combination of chitosan and the specific cationic
LIN ET AL. 21 of 26
F I G U R E 11 Cationic substituted chitosan polymers capable of

inactivating human coronaviruses.201
quarternary ammonium substituent appears to be essen-

tial for its activity, as unfunctionalized chitosan, 𝜄- and
𝜅-carrageenans and heparin were ineffective in vitro despite
their ionic nature. The chitosan derivatives bearing different
degrees of substitution were also highly selective in their viru-
cidal activity, being effective against only murine hepatitis
virus and a number of human coronaviruses (HCoV-NL63,
HCoV-229E, HCoV-OC43, and HCoV-HKU1).202 Their
virus inhibition occurred from the formation of a complex
with the S protein of the coronaviruses, which prevents the
viruses from binding to its cellular receptor for infection.
5.4 Disinfectants for inactivating airborne

viruses
Airborne transmission of viruses is another major route of

human-to-human transmissions and can occur in the form
of aerosols (a cut-off droplet size of < 5 μm is typically
chosen).203 These aerosol microdroplets settle slowly from the
air, and as long as the virus particles remain viable, are res-
pirable and can result in direct viral transmission to the alve-
olar region. The airborne stability of viruses varies greatly,
F I G U R E 9 Inactivation of enveloped viruses by (A) hydrophobic
charged PEI derivatives;197 and (B) pyridinium-type polymers. Figure
and depends on relative humidity and temperature. Lower
adapted from ref. 198. Counterions on the charged polymers are not humidity is generally favorable for viruses with more lipids,
shown whilst viruses with low or no lipid content show stability
at higher humidity.204 The effects of humidity on virus sta-
bility is also dependent on temperature- for instance, lower
temperatures can enhance the stability of non-enveloped rhi-
noviruses at high relative humidity.205 Airborne transmission
is one of the major routes of transmission of the enveloped
Influenza A virus,206 and has been implicated in SARS-CoV-
1 superspreading events during the 2002–2004 outbreak.207
A recent study has also revealed that the Covid-19-causing
SARS-CoV-2 virus possesses similar aerosol stabilities as
the SARS-CoV-1, remaining viable for the 3-hour duration
of study.16 Furthermore, given the high momentum of the
multiphase turbulent gas cloud emitted from sneezing and
F I G U R E 10 Inactivation of non-enveloped adenoviruses using coughing, virus-laden droplets may possibly be spread for
quarternary phosphonium polymers. Figure adapted from Ref.200 with distances larger than the 1–2 m recommended separation for
permission from The Royal Society of Chemistry SARS-CoV-2.208 In fact, SARS-CoV-2 virus particles were
found in the ventilation systems of the hospital rooms housing
22 of 26 LIN ET AL.
Covid-19 patients in China.209 Clearly, methods and disin- towards a broad range of viruses with fast-action and high
fectants capable of disinfecting the air are thus valuable in potency but still suitable for long-term use, exhibiting good
limiting viral transmissions, especially within indoor environ- biocompatibility and mild effects towards surfaces. A poten-
ments. tial direction may be to develop potent disinfectant agents
Methods for disinfecting indoor air is currently an active from natural compounds218 as they may have less toxicity
field of research, though much more remains to be under- allowing the product to be child-safe219 and also safe for
stood, and no perfect solutions yet exist. While UVGI can be long-term usage. New generation sanitizers with viral inacti-
effective and efficient in inactivating viruses in aerosols,210 vation mechanisms that can enhance and balance broad dis-
it can also lead to significant skin and eye discomfort.211 infection efficacy with biocompatibility are thus likely to
Photocatalyst (silver ion-doped TiO2 )-coated air filters212 and have good potential in becoming the preferred choice of
ionisers213 have also been recently studied and demonstrated consumers.
to be effective in removing viable viruses from the air, though
they are not expected to be stand-alone solutions. Thus far, CO N F L I C T O F I N T E R E ST
very few chemical disinfecting agents have been studied for The authors declare no conflict of interest.
inactivating airborne viruses.
In 2016, the use of extremely low concentrations of O RC I D
chlorine dioxide (ClO2 ) was reported to inactivate airborne Xian Jun Loh https://orcid.org/0000-0001-8118-6502
viruses.214 Using the model bacteriophage viruses (MS2 and
ΦX174), 0.01 and 0.02 ppm of ClO2 could reduce the num- REFERENCES
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Received: 13 March 2020 Revised: 2 April 2020 Accepted: 5 April 2020

Sanitizing agents for virus inactivation and disinfection

1 SoftMaterials Department, Institution of

1 I N T RO D U C T I O N catastrophe, with more than 50 million deaths and 500 million

VIEW. 2020;1:e16. wileyonlinelibrary.com/journal/viw2 1 of 26

2 G E N E R A L WOR K I NG 2.3 Factors affecting disinfectant efficacy

TABLE 1 Viruses and common diseases

household disinfectants and detergents and have been demon-

3.2.1 Cationic surfactants (Quaternary

Quaternary ammonium compounds (QACs) form the main

organic matter contamination.46 LAS is able to effectively

Zwitterionic surfactants are molecules bearing both

3.3 Oxidizing agents

Disinfectants such as sodium hypochlorite, hydrogen perox-

Sodium hypochlorite, the active ingredient in household

F I G U R E 4 Chemical structures of (A) Sodium hypochlorite (B)

3.4 Peracetic acid

Peracetic acid decomposes in an analogous manner to form

settings, personal non-staining 137

70.0 Feline Calicivirus (F9) 5 min 2.6±0.3 - 137

70.0 Human immunodeficient virus 1 min >5.50 R.T. 138

70.0 Influenza A (H1N1) 1 min ≥4.84 20 139

60.0 Vaccinia virus strain Lister 1 min ≥4.38 ± 0.37 20 - 22 140

Elstree (ATCC VR-1549)

60.0 Modified vaccinia Ankara strain 1 min ≥5.40 ± 0.36 20 - 22 140

70.0 Mouse hepatitis virus (MHV) - 3.92 - 40

70.0 Transmissible gastroenteritis - 3.19 - 40

settings, personal non-staining 137

specific concentration range to

Elstree (ATCC VR-1549)

60.0 Modified vaccinia Ankara strain 1 min ≥5.40 ± 0.36 20 - 22 140

– Quaternary household non-caustic. Requires warmer 22

reduced by the presence of Type 1

0.2 Human Coxsackie virus 1 min >5.12 R.T. 22

0.2 Human Coronavirus 1 min 0.0 R.T. 22

0.2 Human Coronavirus ATCC 10 min 0.0 R.T. 22

VR-759 (Strain OC43)

0.05 Murine Hepatitis Virus (Strains 10 min >3.7 23 9

MHV-2 and MHV-N)

0.05 Canine coronavirus (Strain 1–71) 10 min >3.7 23 9

>0.05 Equine herpesvirus type 1 10 min 99% 23 - 25 44a

0.1 Human Adenovirus Type 3 1h 5.02 ± 1.57 33 42

0.1 Human Adenovirus Type 4 1h 2.94 ± 0.80 33 42

0.1 Human Adenovirus Type 5 1h 5.27 ± 0.73 33 42

0.1 Human Adenovirus Type 5 1h 3.65 ± 1.04 33 42

0.1 Human Adenovirus Type 7a 1h 3.71 ± 1.87 33 42

0.1 Human Adenovirus Type 8 1h 1.80 ± 1.12 33 42

0.1 Human Adenovirus Type 8 1h 1.01 ± 0.50 33 42

0.1 Human Adenovirus Type 19/64 1h 3.66 ± 1.46 33 42

0.1 Human Adenovirus Type 37 1h 4.23 ± 0.21 33 42

0.025 Equine herpesvirus type 1 1h 99% 23 - 25 44a

0.0125 Equine herpesvirus type 1 10 min 99% 23 - 25 44a

0.00175 Canine coronavirus (Strain S378) 3 days 3.0 37 9

ammonium chloride household non-caustic. Requires warmer 46

unaffected by organic load.

ammonium methylene household non-caustic. Requires warmer

alkylbenzene sulfonate foaming agent in reduced by organic load. 46

Surfactants polyethoxy ethanol emulsifiers spermicidal, dilutions by >500 44