Antiviral Drugs

Chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The recent advancement of direct-acting Antiviral Agents (DAAs) in hepatitis C therapy, resulted in sustained virological response rates of over 90% in treated patients in different stages of liver fibrosis. The efficacy of DAAs treatment has also been confirmed in real-life cohorts that include subjects with decompensated cirrhosis and therefore seems a promising step to a significant reduction in the recurrence of HCC in patients who achieved complete destruction of the HCC nodules by local therapy. We present a 72-year old patient with HCV-related liver cirrhosis who successfully responded to DAAs treatment after complete destruction of an early HCC nodule.

The DNA polymerase and ribonuclease H (RNase H) activities of human immunodeficiency virus type 1 (HIV-1) are needed for the replication of the viral genome and are validated drug targets. However, there are no approved drugs inhibiting RNase H and the efficiency of DNA polymerase inhibitors can be diminished by the presence of drug resistance mutations. In this context, drugs inhibiting both activities could represent a significant advance towards better anti-HIV therapies. We report on the mechanisms of allosteric inhibition of a newly synthesized isatin-based compound designated as RMNC6 that showed IC 50 values of 1.4 and 9.8 μM on HIV-1 RT-associated RNase H and polymerase activities, respectively. Blind docking studies predict that RMNC6 could bind two different pockets in the RT: one in the DNA polymerase domain (partially overlapping the non-nucleoside RT inhibitor [NNRTI] binding pocket), and a second one close to the RNase H active site. Enzymatic studies showed that RMNC6 interferes with efavirenz (an approved NNRTI) in its binding to the RT polymerase domain, although NNRTI resistance-associated mutations such as K103N, Y181C and Y188L had a minor impact on RT susceptibility to RMNC6. In addition, despite being naturally resistant to NNRTIs, the polymerase activity of HIV-1 group O RT was efficiently inhibited by RMNC6. The compound was also an inhibitor of the RNase H activity of wild-type HIV-1 group O RT, although we observed a 6.5-fold increase in the IC 50 in comparison with the prototypic HIV-1 group M subtype B enzyme. Mutagenesis studies showed that RT RNase H domain residues Asn474 and Tyr501, and in a lesser extent Ala502 and Ala508, are critical for RMNC6 inhibition of the endonuclease activity of the RT, without affecting its DNA polymerization activity. Our results show that RMNC6 acts as a dual inhibi-tor with allosteric sites in the DNA polymerase and the RNase H domains of HIV-1 RT.

The well known anticoagulant agent, Heparin, is a member of the polyanionic polysaccharides
called glycosaminoglycans (GAGs). The molecule consists of alternating hexuronic acid and d-glucosamine residues joined by glycosidic linkages (Young, 2008). This gives heparin the appearance of a long, linear sulfated chain with the highest negative charge density of any known biomolecule (Hippensteel et al, 2020). The anticoagulant activity of heparin is attributed to a 3-O-sulfate and 6-O-sulfate containing pentasaccharide sequence or a minimum eight-repeating disaccharide units containing the pentasaccharide sequence which can establish binding sites that allow heparin to selectively and strongly interact with various proteins (Hao et al, 2019). The most well-characterized protein interaction is with the serine protease inhibitor called antithrombin-III (AT3), which gives heparin the ability to catalyze the inactivation of factor Xa or thrombin (Hippensteel et al, 2020). This simultaneously inhibits both thrombin generation and thrombin activity in the blood circulation, thus inhibiting blood coagulation. Since coagulation has been found to be particularly active early in the course of the novel Coronavirus Disease 2019 (COVID-19), anticoagulant therapy has proven to have the greatest impact before the disease advances to the hyperinflammatory state that can characterize the later stages of the disease (Antiviral Therapy, n.d). The high affinity interaction of heparin with a variety of proteases can characterize heparin with many other pharmacological properties such as anti-inflammatory, anti-viral, anti-angiogenesis, anti-neoplastic, and antimetastatic effects (Hao et al, 2019). Despite the mounting investigation of heparin’s effectiveness in treating the adverse side effects of COVID-19, there is still limited clinical data linking heparin therapy to meaningful antiviral outcomes. Hence, this paper evaluates the significant potential of heparin as an antiviral agent to inhibit the entry of the SARS-CoV-2 virus and thus revolutionize therapy for COVID-19.

The goal of antiviral treatment for chronic hepatitis B (CHB) is to reduce the risk of liver-related complications, including liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). It is not possible to eliminate hepatitis B virus from the host with currently available antiviral treatments; hence, a realistic goal is to decrease the risk of HCC as much as possible with an appropriate and timely antiviral treatment. For the past decades, real-world evidence has enlarged the field of CHB research. Presently, there is mounting evidence that randomized clinical trials are not technically and ethically possible to conduct. In this review, we focus on secondary prevention by antiviral treatment in patients with CHB, mainly based on real-world evidence.

This study evaluated the inhibition property of concentrates from Aframomium melegueta K.Schum and Vernonia amygdalina Delile against the proliferation of atypical Fowlpox virus strain (FPV Kabete) in Embryonated chick eggs (ECEs). We determined the effect of the concentrates on the propagation of the atypical FPV in ECEs via virus inhibition assay and linked the possible mechanisms by which compounds present in the concentrates were able to reduce the levels of cytopathic effect expressions caused by the atypical FPV in ECEs. The results showed that the concentrates had multiple inhibitory effects against the FPV while they showed mild toxicities in chick embryos with toxic threshold concentration set at 300 µM. In summary, the A. melegueta concentrate had stronger inhibitory effect against the FPV proliferation; it increased the average embryo weight (from 12.56 ± 1.61 g to 23.19 ± 1.79 g) and diminished the FPV Log 10 EID 50 titer from 3.86 to 3.08. It also reduced the mean number of pock lesions from 18.28 ± 1.84 pfu/100EID 50 to 2.19 ± 0.65 pfu/100EID 50 and likewise reducing the mean pock diameter from 22.48 ± 2.74 mm to 4.89 ± 1.04 mm. Comparatively, the V. amygdalina concentrate showed lesser inhibitory effect than the A. melegueta concentrate; it increased the average embryo weight (from 12.56 ± 1.61 g to 19.49 ± 1.33 g), diminished the FPV Log 10 EID 50 titer from 3.86 to 3.34, reduced the mean number of pock lesions from 18.28 ± 1.84 pfu/100EID 50 to 6.85 ± 1.77 pfu/100EID 50 and likewise reducing the mean pock diameter from 22.48 ± 2.74 mm to 8.96 ± 1.26 mm. This study showed the efficacy of the concentrates to inhibit the proliferation of the FPV in ECEs and that compounds contained in the concentrate can lead the discovery for biosynthesis of novel anti-poxvirus inhibitors.

Just allocation of resources for control of infectious diseases can be profoundly influenced by the dynamics of those diseases. In this paper we discuss the use of antiviral drugs for treatment of pandemic influenza. While the primary effect of such drugs is to alleviate and shorten the duration of symptoms for treated individuals, they can have a secondary effect of reducing transmission in the community. However, existing stockpiles may be insufficient for all clinical cases. Here we use simple mathematical models to present scenarios where the optimum policies to minimise morbidity and mortality, with a limited drug stockpile, are not always the most intuitively obvious and may conflict with theories of justice. We discuss ethical implications of these findings.