Open Access by Adriano Mollica
Bentham Science Publishers
Biphalin (Tyr-D-Ala-Gly-Phe-NH-NH<-Phe<-Gly<-D-Ala<-Tyr) is an opioid octapeptide with a dimeric ... more Biphalin (Tyr-D-Ala-Gly-Phe-NH-NH<-Phe<-Gly<-D-Ala<-Tyr) is an opioid octapeptide with a dimeric structure based on two identical pharmacophore portions, derived from enkephalins, joined “tail to tail” by a hydrazide bridge. This particular structure enhances the antinociceptive activity of the native enkephalins with an unknown mechanism, probably based on a cooperative binding and improved enzymatic stability. Biphalin has excellent binding affinity for μ and δ receptors and it is a highly potent analgesic, as potent as or more than ethorphine. A definitive explanation of the extraordinary in vivo potency shown by this compound, which has pronounced efficacy in pain modulation, is still not available; it has been suggested, however, that the high agonist activity may be related to its binding mode at both μ and δ opioid receptors. Biphalin has significantly higher potency than other analgesics with novel biological profiles; in particular, most recent data show that biphalin is unlikely to produce dependency in chronic use. In the past 20 years, there have been many attempts to modify its structure to obtain products unaffected by the action of enkephalinases, to enhance its antinociceptive activity and to modify the BBB penetration. In addition, structure-activity relationship studies (SAR) were performed in order to understand the elements responsible for biphalin’s high activity. The aim of the studies reported in this review was to clarify: i) the role of the hydrazide bridge, ii) the role of residues in position 4, 4’ and 3, 3’, iii) the consequences of molecular simplifications (truncation, delection), iv) the consequences of cyclization through a disulfide bridge, v) conjugation with PEG and fluorescet residues, and vi) radiolabeling on Tyr1.
Papers by Adriano Mollica
SSRN Electronic Journal, 2022
Antioxidants
Common bean (Phaseolus vulgaris) represents one of the most famous foods with antiobesity activit... more Common bean (Phaseolus vulgaris) represents one of the most famous foods with antiobesity activity showing a significant efficacy against fat accumulation, insulin resistance and dyslipidaemia. In this work, two Italian varieties of common bean, i.e., Tondino del Tavo and Cannellino Bio, from the centre of Italy were studied to characterise their phenolic profile by HPLC-PDA in relation to different fractions after a straightforward extraction procedure. Antioxidant property and enzymatic inhibition power were also evaluated in order to delineate a possible biological profile. Results show a considerable phenolic content (0.79 and 1.1 µg/mg of 3-hydroxybenzoic acid for hexane extract of Tondino del Tavo and Cannellino Bio, respectively; 0.30 µg/mg p-coumaric acid for n-hexane extract of Tondino del Tavo) for both varieties, and a strong antioxidant activity according to the major phenolic concentration of the extracts. The anti-inflammatory activity of the decoction extracts was als...
Life
Ecdysteroids represent arthropods’ steroidal hormones, and they exist in about 5–6% of plant spec... more Ecdysteroids represent arthropods’ steroidal hormones, and they exist in about 5–6% of plant species. In this study, the enzyme inhibitory activity of 20 ecdysteroids was assessed for the first time via determining their inhibition versus acetylcholinesterase, butyrylcholinesterase, tyrosinase, as well as α-amylase enzymes. Furthermore, 20-Hydroxyecdysone-2,3,22-tri-O-acetate (4) showed the highest inhibition of acetylcholinesterase and butyrylcholinesterase with values of 5.56 and 4.76 mg GALAE/g, respectively. All ecdysteroids displayed tyrosinase inhibitory effects, whereas the most potent was viticosterone E (7) with 78.88 mg KAE/g. Most ecdysteroids had similar amylase inhibitory properties; meanwhile, the best α-amylase inhibitory potential was observed with viticosterone E-diacetonide (18) (0.35 mmol ACAE/g). Most of the tested compounds showed tyrosinase inhibitory potential; therefore, they were exposed to molecular docking evaluation using the tyrosinase enzyme. Viticoster...
Molecules
Phenylpropanoid glycosides are a class of natural substances of plant origin with interesting bio... more Phenylpropanoid glycosides are a class of natural substances of plant origin with interesting biological activities and pharmacological properties. This study reports the antinociceptive and anti-inflammatory effects of calceolarioside A, a phenylpropanoid glycoside previously isolated from various Calceolaria species. In models of acute nociception induced by thermal stimuli, such as the hot plate and tail flick test, calceolarioside administered at doses of 1, 5, and 10 μg in the left cerebral ventricles did not modify the behavioral response of mice. In an inflammatory based persistent pain model as the formalin test, calceolarioside A at the high dose tested (100 μg/paw) reduced the licking activity induced by formalin by 35% in the first phase and by 75% in the second phase of the test. In carrageenan-induced thermal hyperalgesia, calceolarioside A (50 and 100 μg/paw) was able to significantly reverse thermal hyperalgesia induced by carrageenan. The anti-inflammatory activity o...
International Journal of Molecular Sciences, 2022
Elastases are a broad group of enzymes involved in the lysis of elastin, the main component of el... more Elastases are a broad group of enzymes involved in the lysis of elastin, the main component of elastic fibres. They are produced and released in the human body, mainly by neutrophils and the pancreas. The imbalance between elastase activity and its endogenous inhibitors can cause different illnesses due to their excessive activity. The main aim of this review is to provide an overview of the latest advancements on the identification, structures and mechanisms of action of peptide human neutrophil elastase inhibitors isolated from natural sources, such as plants, animals, fungi, bacteria and sponges. The discovery of new elastase inhibitors could have a great impact on the pharmaceutical development of novel drugs through the optimization of the natural lead compounds. Bacteria produce mainly cyclic peptides, while animals provide for long and linear amino acid sequences. Despite their diverse natural sources, these elastase inhibitors show remarkable IC50 values in a range from nM t...
Copyright © 2012 Ivana Cacciatore et al. This is an open access article distributed under the Cre... more Copyright © 2012 Ivana Cacciatore et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease(AD), are a group of pathologies characterized by a progressive and specific loss of certain brain cell populations. Oxidative stress, mitochondrial dysfunction, and apoptosis play interrelated roles in these disorders. It is well documented that free radical oxidative damage, particularly on neuronal lipids, proteins, DNA, and RNA, is extensive in PD and AD brains. Moreover, alterations of glutathione (GSH) metabolism in brain have been implicated in oxidative stress and neurodegenerative diseases. As a consequence, the reduced GSH levels observed in these pathologies have stimulated a number of researchers to find new potential approaches for main...
Angewandte Chemie International Edition, 2021
G protein-coupled receptors (GPCRs) represent an important group of membrane proteins that play a... more G protein-coupled receptors (GPCRs) represent an important group of membrane proteins that play a central role in modern medicine. Unfortunately, conformational promiscuity hampers full therapeutic exploitation of GPCRs, since the largest population of the receptor will adopt a basal conformation, which subsequently challenges screens for agonist drug discovery programs. Here, we describe a set of peptidomimetics able to mimic the ability of G proteins in stabilizing the active state of the β 2 adrenergic receptor (β 2 AR) and the dopamine 1 receptor (D1R). During fragment-based screening efforts, these (un)constrained peptide analogues of the α 5 helix in G s proteins, were able to identify agonism pre-imprinted fragments for the examined GPCRs, and as such, they behave as a generic tool, enabling an engagement in agonist earmarked discovery programs.
Antioxidants, 2021
The Mediterranean diet comprises a set of foods that commonly feature in the diet of inhabitants ... more The Mediterranean diet comprises a set of foods that commonly feature in the diet of inhabitants from countries bordering the Mediterranean Sea [...].
Biomolecules, 2019
The endocannabinoid system represents an integrated neuronal network involved in the control of s... more The endocannabinoid system represents an integrated neuronal network involved in the control of several organisms’ functions, such as feeding behavior. A series of hybrids of 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (mimonabant), a well-known inverse agonist of the type-1 cannabinoid receptor (CB1), once used as an antiobesity drug, and the N-(2S)-substitutes of 1-[(4-fluorophenyl)methyl]indazole-3-carboxamide with 1-amino-3-methyl-1-oxobutane (AB-Fubinaca), 1-amino-3,3-dimethyl-1-oxobutane (ADB-Fubinaca), and 3-methylbutanoate (AMB-Fubinaca), endowed with potent agonistic activity towards cannabinoid receptors CB1 and CB2 were in solution as C-terminal amides, acids, methyl esters and N-methyl amides. These compounds have been studied by binding assays to cannabinoid receptors and by functional receptor assays, using rat brain membranes in vitro. The most active among them as an agonist, (S)-1-(2,4-dichlorobenzyl)-N-(3,3-dimet...
Food and Chemical Toxicology, 2019
Scientific Reports, 2019
Here, we report the chemical synthesis of two DPDPE analogues 7a (NOVA1) and 7b (NOVA2). This ent... more Here, we report the chemical synthesis of two DPDPE analogues 7a (NOVA1) and 7b (NOVA2). This entailed the solid-phase synthesis of two enkephalin precursor chains followed by a CuI-catalyzed azide-alkyne cycloaddition, with the aim of improving in vivo analgesic efficacy versus DPDPE. NOVA2 showed good affinity and selectivity for the μ-opioid receptor (KI of 59.2 nM, EC50 of 12.9 nM, EMax of 87.3%), and long lasting anti-nociceptive effects in mice when compared to DPDPE.
International Journal of Food Properties, 2017
Protein & Peptide Letters, 2016
The endocannabinoid system is activated by the binding of natural arachidonic acid derivatives (e... more The endocannabinoid system is activated by the binding of natural arachidonic acid derivatives (endogenous cannabinoids or endocannabinoids) as lipophilic messengers to cannabinoid receptors CB1 and CB2. The endocannabinoid system comprises also many hydrolytic enzymes responsible for the endocannabinoids cleavage, such as FAAH and MAGL. These two enzymes are possible therapeutic targets for the development of new drugs as indirect cannabinoid agonists. Recently a new family of endocannabinoid modulators was discovered; the lead of this family is the nonapeptide hemopressin produced from enzymatic cleavage of the α-chain of hemoglobin and acting as negative allosteric modulator of CB1. Hemopressin shows several physiological effects, e.g. antinociception, hypophagy, and hypotension. It is still matter of debate whether this peptide, isolated from the brain of rats is a real neuromodulator of the endocannabinoid system. Recent evidence indicates that hemopressin could be a by-product formed by chemical degradation of a longer peptide RVD-hemopressin during the extraction from the brain homolysate. Indeed, RVD-hemopressin is more active than hemopressin in certain biological tests and may bind to the same subsite as Rimonabant, which is an inverse agonist for the CB1 receptor and a μ-opioid receptor antagonist. These findings have stimulated several studies to verify this hypothesis and to evaluate possible therapeutic applications of hemopressin, its peptidic derivatives and synthetic analogues, opening new perspectives to the development of novel cannabinoid drugs.
Journal of Receptors and Signal Transduction, 2016
Abstract Visceral leishmaniasis (VL) is the most fatal form of leishmaniasis and it affects 70 co... more Abstract Visceral leishmaniasis (VL) is the most fatal form of leishmaniasis and it affects 70 countries worldwide. Increasing drug resistant for antileishmanial drugs such as miltefosine, sodium stibogluconate and pentamidine has been reported in the VL endemic region. Amphotericin B has shown potential antileishmanial activity in different formulations but its cost of treatment and associated nephrotoxicity have limited its use by affected people living in the endemic zone. To control the VL infection in the affected countries, it is necessary to develop new antileishmanial compounds with high efficacy and negligible toxicity. Computer aided programs such as binding free energy estimation; ADMET prediction and molecular dynamics simulation can be used to investigate novel antileishmanial molecules in shorter duration. To develop antileishmanial lead molecule, we performed standard precision (SP) docking for 1160 benzoxaborole analogs along with reference inhibitors against trypanothione reductase of Leishmania parasite. Furthermore, extra precision (XP) docking, ADMET prediction, prime MM-GBSA was conducted over 115 ligands, showing better docking score than reference inhibitors to get potential antileishmanial compounds. Simultaneously, area under the curve (AUC) was estimated using ROC plot to validate the SP and XP docking protocol. Later on, two benzoxaborole analogs with best MM-GBSA ΔG-bind were subjected to molecular simulation and docking confirmation to ensure the ligand interaction with TR. The presented drug discovery based on computational study confirms that BOB27 can be used as a potential drug candidate and warrants further experimental investigation to fight against VL in endemic areas.
Industrial Crops and Products, 2015
Journal of Functional Foods, 2018
Life, 2022
Formyl peptide receptor type 2 (FPR2/ALX) belongs to the formyl peptide receptors (FPRs) family c... more Formyl peptide receptor type 2 (FPR2/ALX) belongs to the formyl peptide receptors (FPRs) family clustered on chromosome 19 and encodes a family of three Class A of G protein-coupled receptors (GPCRs). A short N-terminal region, an NPXXY motif in transmembrane (TM) region 7 and an E/DRY motif that bridges TM3 and TM6 stabilizing inactive receptor conformations characterize this class of receptors. In recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), FPRs play a crucial role in innate immune responses. FPR2/ALX is highly expressed in myeloid cells, as well as in chondrocytes, fibroblasts, endothelial, epithelial and smooth muscle cells. FPR2/ALX mRNA expression was recently reported in the rat brainstem, spinal cord, thalamus/hypothalamus, cerebral neocortex, hippocampus, cerebellum and striatum. The central nervous system (CNS) distribution of FPR2/ALX suggests important functions in nociception. Thus, the present study was c...
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Open Access by Adriano Mollica
Papers by Adriano Mollica