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Effect of ribavirin on zidovudine efficacy and toxicity in vitro: a concentration-dependent interaction

Sim SM, Hoggard PG, Sales SD, Phiboonbanakit D, Hart CA, Back DJ

AIDS Res Hum Retroviruses, 1998 Dec 20;14(18):1661-7.
PMID: 9870320

Zidovudine (ZDV) is converted to its active triphosphate (ZDVTP) by intracellular kinases. The intermediate ZDV monophosphate (ZDVMP) is believed to play a major role in ZDV toxicity. Manipulation of ZDV phosphorylation is a possible therapeutic strategy for altering the risk-benefit ratio. Here we investigate whether combining RBV with ZDV is able to modulate efficacy and toxicity of ZDV. We have measured the intracellular activation of ZDV (0.3 microM) in the absence and presence of ribavirin (RBV; 2 and 20 microM) in Molt 4 and U937 cells. MTT cytotoxicity of ZDV (10-1000 microM) was also measured with and without RBV (2 microM) in Molt 4 and U937 cells. Measurement of endogenous deoxythymidine triphosphate (dTTP) allowed investigation of the dTTP/ZDVTP ratio. The antiviral efficacy of ZDV in combination with RBV (2 microM) was assessed by HIV p24 antigen measurements. In the presence of RBV (2 and 20 microM) a decrease in total ZDV phosphates was observed, owing mainly to an effect primarily on ZDVMP rather than the active ZDVTP. RBV also increased endogenous dTTP pools in both cell types, resulting in an increase in the dTTP/ZDVTP ratio. ZDV alone significantly reduced p24 antigen production, with an IC50 of 0.34 microM. Addition of RBV increased the IC50 approximately fivefold (1.52 microM). However, at higher concentrations of ZDV (10 and 100 microM) the antagonistic effect of RBV (2 microM) on ZDV was lost. The RBV-mediated decrease in ZDVMP may explain the reduction in ZDV toxicity when combined with RBV (2 microM). Cytotoxicity of ZDV was reduced in the presence of RBV (2 microM) at all concentrations in both cell lines, probably owing to saturation of ZDVTP formation. The interaction of ZDV and RBV is concentration dependent.

Matched MeSH terms: Antiviral Agents/pharmacology*
Methods in Screening Antiviral Drugs Against Enterovirus 71

Bajaber NAOA, Ramanathan B

Methods Mol Biol, 2021;2296:167-184.
PMID: 33977447 DOI: 10.1007/978-1-0716-1358-0_9

Enteroviruses 71 (EV71) is a single-stranded, neurotrophic RNA virus responsible for the numerous outbreaks of hand, foot, and mouth disease (HFMD) in the Asia-Pacific regions. HFMD primarily affects children to cause range of infection, from mild symptoms to acute flaccid paralysis, and hemorrhage. Despite increased incidence of EV71 epidemics globally and research against EV71 becoming prioritized, no antiviral agent against EV71 has yet been licensed and approved worldwide. In this chapter, detailed EV71 antiviral screening techniques are described, including plaque assay which determines viral titers through the use of a semisolid overlay, carboxymethyl cellulose to allow even viral spread and infection across the host cellular monolayers as well as a crystal violet, a distinct counterstain to visualize circular regions of infectious zones-plaques. qRT-PCR is used to quantify the viral genomic RNA in the infected samples and MTS cell viability assay to quantify the cell viability after infection or toxicity of the compound on the cells. Furthermore, various antiviral inhibition assays including prophylactic, post infection, and virucidal assays are demonstrated for estimation of the antiviral activity of potential antiviral drugs against EV71. These methods can be effectively utilized in virology laboratories for effective high-throughput screening of antiviral molecules against EV71 that can assist in the future development of antiviral drugs.

Matched MeSH terms: Antiviral Agents/pharmacology*
Fulltext Antivirals blocking entry of enteroviruses and therapeutic potential

Anasir MI, Zarif F, Poh CL

J Biomed Sci, 2021 Jan 15;28(1):10.
PMID: 33451326 DOI: 10.1186/s12929-021-00708-8

Viruses from the genus Enterovirus (EV) of the Picornaviridae family are known to cause diseases such as hand foot and mouth disease (HFMD), respiratory diseases, encephalitis and myocarditis. The capsid of EV is an attractive target for the development of direct-acting small molecules that can interfere with viral entry. Some of the capsid binders have been evaluated in clinical trials but the majority have failed due to insufficient efficacy or unacceptable off-target effects. Furthermore, most of the capsid binders exhibited a low barrier to resistance. Alternatively, host-targeting inhibitors such as peptides derived from the capsid of EV that can recognize cellular receptors have been identified. However, the majority of these peptides displayed low anti-EV potency (µM range) as compared to the potency of small molecule compounds (nM range). Nonetheless, the development of anti-EV peptides is warranted as they may complement the small-molecules in a drug combination strategy to treat EVs. Lastly, structure-based approach to design antiviral peptides should be utilized to unearth potent anti-EV peptides.

Matched MeSH terms: Antiviral Agents/pharmacology*
Fulltext Characterization of β-d-N4-Hydroxycytidine as a Novel Inhibitor of Chikungunya Virus

Ehteshami M, Tao S, Zandi K, Hsiao HM, Jiang Y, Hammond E, et al.

Antimicrob Agents Chemother, 2017 04;61(4).
PMID: 28137799 DOI: 10.1128/AAC.02395-16

Chikungunya virus (CHIKV) represents a reemerging global threat to human health. Recent outbreaks across Asia, Europe, Africa, and the Caribbean have prompted renewed scientific interest in this mosquito-borne alphavirus. There are currently no vaccines against CHIKV, and treatment has been limited to nonspecific antiviral agents, with suboptimal outcomes. Herein, we have identified β-d-N4-hydroxycytidine (NHC) as a novel inhibitor of CHIKV. NHC behaves as a pyrimidine ribonucleoside and selectively inhibits CHIKV replication in cell culture.

Matched MeSH terms: Antiviral Agents/pharmacology*
Fulltext Investigation of twenty selected medicinal plants from Malaysia for anti-Chikungunya virus activity

Chan YS, Khoo KS, Sit NWW

Int Microbiol, 2016 Sep;19(3):175-182.
PMID: 28494087 DOI: 10.2436/20.1501.01.275

Chikungunya virus is a reemerging arbovirus transmitted mainly by Aedes mosquitoes. As there are no specific treatments available, Chikungunya virus infection is a significant public health problem. This study investigated 120 extracts from selected medicinal plants for anti-Chikungunya virus activity. The plant materials were subjected to sequential solvent extraction to obtain six different extracts for each plant. The cytotoxicity and antiviral activity of each extract were examined using African monkey kidney epithelial (Vero) cells. The ethanol, methanol and chloroform extracts of Tradescantia spathacea (Commelinaceae) leaves showed the strongest cytopathic effect inhibition on Vero cells, resulting in cell viabilities of 92.6% ± 1.0% (512 μg/ml), 91.5% ± 1.7% (512 μg/ml) and 88.8% ± 2.4% (80 μg/ml) respectively. However, quantitative RT-PCR analysis revealed that the chloroform extract of Rhapis excelsa (Arecaceae) leaves resulted in the highest percentage of reduction of viral load (98.1%), followed by the ethyl acetate extract of Vernonia amygdalina (Compositae) leaves (95.5%). The corresponding 50% effective concentrations (EC50) and selectivity indices for these two extracts were 29.9 ± 0.9 and 32.4 ± 1.3 μg/ml, and 5.4 and 5.1 respectively. Rhapis excelsa and Vernonia amygdalina could be sources of anti-Chikungunya virus agents. [Int Microbiol 19(3):175-182 (2016)].

Matched MeSH terms: Antiviral Agents/pharmacology*
A new adaptive L1-norm for optimal descriptor selection of high-dimensional QSAR classification model for anti-hepatitis C virus activity of thiourea derivatives

Algamal ZY, Lee MH

SAR QSAR Environ Res, 2017 Jan;28(1):75-90.
PMID: 28176549 DOI: 10.1080/1062936X.2017.1278618

A high-dimensional quantitative structure-activity relationship (QSAR) classification model typically contains a large number of irrelevant and redundant descriptors. In this paper, a new design of descriptor selection for the QSAR classification model estimation method is proposed by adding a new weight inside L1-norm. The experimental results of classifying the anti-hepatitis C virus activity of thiourea derivatives demonstrate that the proposed descriptor selection method in the QSAR classification model performs effectively and competitively compared with other existing penalized methods in terms of classification performance on both the training and the testing datasets. Moreover, it is noteworthy that the results obtained in terms of stability test and applicability domain provide a robust QSAR classification model. It is evident from the results that the developed QSAR classification model could conceivably be employed for further high-dimensional QSAR classification studies.

Matched MeSH terms: Antiviral Agents/pharmacology*
Fulltext Neuraminidase Inhibitor of Garcinia atroviridis L. Fruits and Leaves Using Partial Purification and Molecular Characterization

Muchtaridi M, Nuwarda RF, Ikram EHK, Abdul Rahim AS, Gazzali AM, Wahab HA

Molecules, 2022 Jan 30;27(3).
PMID: 35164214 DOI: 10.3390/molecules27030949

Neuraminidase (NA) is an enzyme that prevents virions from aggregating within the host cell and promotes cell-to-cell spread by cleaving glycosidic linkages to sialic acid. The best-known neuraminidase is the viral neuraminidase, which present in the influenza virus. Thus, the development of anti-influenza drugs that inhibit NA has emerged as an important and intriguing approach in the treatment of influenza. Garcinia atroviridis L. (GA) dried fruits (GAF) are used commercially as seasoning and in beverages. The main objective of this study was to identify a new potential neuraminidase inhibitor from GA. A bioassay-guided fractionation method was applied to obtain the bioactive compounds leading to the identification of garcinia acid and naringenin. In an enzyme inhibition study, garcinia acid demonstrated the highest activity when compared to naringenin. Garcinia acid had the highest activity, with an IC50 of 17.34-17.53 µg/mL or 91.22-92.21 µM against Clostridium perfringens-NA, and 56.71-57.85 µg/mL or 298.32-304.31 µM against H1N1-NA. Based on molecular docking results, garcinia acid interacted with the triad arginine residues (Arg118, Arg292, and Arg371) of the viral neuraminidase, implying that this compound has the potential to act as a NA enzyme inhibitor.

Matched MeSH terms: Antiviral Agents/pharmacology*
Flavonoids: promising natural compounds against viral infections

Zakaryan H, Arabyan E, Oo A, Zandi K

Arch Virol, 2017 Sep;162(9):2539-2551.
PMID: 28547385 DOI: 10.1007/s00705-017-3417-y

Flavonoids are widely distributed as secondary metabolites produced by plants and play important roles in plant physiology, having a variety of potential biological benefits such as antioxidant, anti-inflammatory, anticancer, antibacterial, antifungal and antiviral activity. Different flavonoids have been investigated for their potential antiviral activities and several of them exhibited significant antiviral properties in in vitro and even in vivo studies. This review summarizes the evidence for antiviral activity of different flavonoids, highlighting, where investigated, the cellular and molecular mechanisms of action on viruses. We also present future perspectives on therapeutic applications of flavonoids against viral infections.

Matched MeSH terms: Antiviral Agents/pharmacology*
Fulltext Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication

Low ZY, Yip AJW, Lal SK

Biochim Biophys Acta Mol Basis Dis, 2022 Feb 01;1868(2):166294.
PMID: 34687900 DOI: 10.1016/j.bbadis.2021.166294

Ivermectin (IVM) is an FDA approved macrocyclic lactone compound traditionally used to treat parasitic infestations and has shown to have antiviral potential from previous in-vitro studies. Currently, IVM is commercially available as a veterinary drug but have also been applied in humans to treat onchocerciasis (river blindness - a parasitic worm infection) and strongyloidiasis (a roundworm/nematode infection). In light of the recent pandemic, the repurposing of IVM to combat SARS-CoV-2 has acquired significant attention. Recently, IVM has been proven effective in numerous in-silico and molecular biology experiments against the infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centres around the inhibition of the cytoplasmic-nuclear shuttling of viral proteins by disrupting the Importin heterodimer complex (IMPα/β1) and downregulating STAT3, thereby effectively reducing the cytokine storm. Furthermore, the ability of IVM to block the active sites of viral 3CLpro and S protein, disrupts important machinery such as viral replication and attachment. This review compiles all the molecular evidence to date, in review of the antiviral characteristics exhibited by IVM. Thereafter, we discuss IVM's mechanism and highlight the clinical advantages that could potentially contribute towards disabling the viral replication of SARS-CoV-2. In summary, the collective review of recent efforts suggests that IVM has a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2.

Matched MeSH terms: Antiviral Agents/pharmacology
Fulltext EGCG as an anti-SARS-CoV-2 agent: Preventive versus therapeutic potential against original and mutant virus

Tsvetkov V, Varizhuk A, Kozlovskaya L, Shtro A, Lebedeva O, Komissarov A, et al.

Biochimie, 2021 Dec;191:27-32.
PMID: 34389380 DOI: 10.1016/j.biochi.2021.08.003

In the search for anti-SARS-CoV-2 drugs, much attention is given to safe and widely available native compounds. The green tea component epigallocatechin 3 gallate (EGCG) is particularly promising because it reportedly inhibits viral replication and viral entry in vitro. However, conclusive evidence for its predominant activity is needed. We tested EGCG effects on the native virus isolated from COVID-19 patients in two independent series of experiments using VERO cells and two different treatment schemes in each series. The results confirmed modest cytotoxicity of EGCG and its substantial antiviral activity. The preincubation scheme aimed at infection prevention has proven particularly beneficial. We complemented that finding with a detailed investigation of EGCG interactions with viral S-protein subunits, including S2, RBD, and the RBD mutant harboring the N501Y mutation. Molecular modeling experiments revealed N501Y-specific stacking interactions in the RBD-ACE2 complex and provided insight into EGCG interference with the complex formation. Together, these findings provide a molecular basis for the observed EGCG effects and reinforce its prospects in COVID-19 prevention therapy.

Matched MeSH terms: Antiviral Agents/pharmacology*
Fulltext Phytochemistry and pharmacological activity of the genus artemisia

Bisht D, Kumar D, Kumar D, Dua K, Chellappan DK

Arch Pharm Res, 2021 May;44(5):439-474.
PMID: 33893998 DOI: 10.1007/s12272-021-01328-4

Artemisia and its allied species have been employed for conventional medicine in the Northern temperate regions of North America, Europe, and Asia for the treatments of digestive problems, morning sickness, irregular menstrual cycle, typhoid, epilepsy, renal problems, bronchitis malaria, etc. The multidisciplinary use of artemisia species has various other health benefits that are related to its traditional and modern pharmaceutical perspectives. The main objective of this review is to evaluate the traditional, modern, biological as well as pharmacological use of the essential oil and herbal extracts of Artemisia nilagirica, Artemisia parviflora, and other allied species of Artemisia. It also discusses the botanical circulation and its phytochemical constituents viz disaccharides, polysaccharides, glycosides, saponins, terpenoids, flavonoids, and carotenoids. The plants have different biological importance like antiparasitic, antimalarial, antihyperlipidemic, antiasthmatic, antiepileptic, antitubercular, antihypertensive, antidiabetic, anxiolytic, antiemetic, antidepressant, anticancer, hepatoprotective, gastroprotective, insecticidal, antiviral activities, and also against COVID-19. Toxicological studies showed that the plants at a low dose and short duration are non or low-toxic. In contrast, a high dose at 3 g/kg and for a longer duration can cause toxicity like rapid respiration, neurotoxicity, reproductive toxicity, etc. However, further in-depth studies are needed to determine the medicinal uses, clinical efficacy and safety are crucial next steps.

Matched MeSH terms: Antiviral Agents/pharmacology
Fulltext Anti-viral activity of culinary and medicinal mushroom extracts against dengue virus serotype 2: an in-vitro study

Ellan K, Thayan R, Raman J, Hidari KIPJ, Ismail N, Sabaratnam V

BMC Complement Altern Med, 2019 Sep 18;19(1):260.
PMID: 31533688 DOI: 10.1186/s12906-019-2629-y

BACKGROUND: Dengue is a mosquito-borne viral infection that has become a major public health concern worldwide. Presently, there is no specific vaccine or treatment available for dengue viral infection.
METHODS: Lignosus rhinocerotis, Pleurotus giganteus, Hericium erinaceus, Schizophyllum commune and Ganoderma lucidium were selected for evaluation of their in-vitro anti-dengue virus serotype 2 (DENV-2) activities. Hot aqueous extracts (HAEs), ethanol extracts (EEs), hexane soluble extracts (HSEs), ethyl acetate soluble extracts (ESEs) and aqueous soluble extracts (ASEs) were prepared from the selected mushrooms. The cytotoxic effects of the extracts were evaluated by the MTT assay. The anti-DENV-2 activities of the extracts were evaluated in three different assays: simultaneous, attachment and penetration assays were perfomed using plaque reduction assays and RT-qPCR assays. The effect of the addition time on viral replication was assessed by the time of addition assay, and a virucidal assay was carried out to evaluate the direct effect of each mushroom extract on DENV-2. The chemical composition of glucans, and the protein and phenolic acid contents in the extracts were estimated.
RESULTS: We found that the HAEs and ASEs of L. rhinocerotis, P. giganteus, H. erinaceus and S. commune were the least toxic to Vero cells and showed very prominent anti-DENV2 activity. The 50% inhibitory concentration (IC50) values of the ASEs ranged between 399.2-637.9 μg/ml, while for the HAEs the range was 312.9-680.6 μg/ml during simultaneous treatment. Significant anti-dengue activity was also detected in the penetration assay of ASEs (IC50: 226.3-315.4 μg/ml) and HAEs (IC50: 943.1-2080.2 μg/ml). Similarly, we observed a marked reduction in the expression levels of the ENV and NS5 genes in the simultaneous and penetration assays of the ASEs and HAEs. Time-of-addition experiments showed that the highest percent of anti-DENV2 activity was observed when the mushroom extracts were added immediately after virus adsorption. None of the extracts exhibited virucidal effect. Chemical composition analysis showed that the major components in the mushroom HAEs and ASEs were glucan (beta D-glucan) and proteins, however, there was no significant correlation between the anti-dengue activity and the concentration of glucans and proteins.
CONCLUSION: These findings demonstrated the potential of mushroom extracts as anti-dengue therapeutic agents with less toxic effects.

Matched MeSH terms: Antiviral Agents/pharmacology*
Antiviral actions of flavanoid-derived compounds on dengue virus type-2

Muhamad M, Kee LY, Rahman NA, Yusof R

Int J Biol Sci, 2010 May 23;6(3):294-302.
PMID: 20567498

Dengue viruses, mosquito-borne members of the Flaviviridae family, are the causative agents of dengue fever and its associated complications, dengue haemorrhagic fever and dengue shock syndrome. To date, more than 2.5 billion people in over 100 countries are at risk of infection, and approximately 20 million infections were reported annually. There is currently no treatment or vaccine available for dengue infection. This study employed a whole-cell organism model or in vitro methods to study the inhibitory property of the flavanoid-derived compounds against DENV2 activity. Results showed that at concentration not exceeding the maximum non-toxic dose (MNTD), these compounds completely prevented DENV2 infection in HepG2 cells as indicated by the absence of cytophatic effects. The in vitro antiviral activity assessed in HepG2 cells employing virus inhibition assay showed high inhibitory activity in a dose dependent manner. At concentration below MNTD, compounds exhibited inhibitory activity against DENV2 with a range of potency strengths of 72% to 100%. The plaque forming unit per ml (pfu/ml) was reduced prominently with a maximum reduction of 98% when the infected HepG2 cells were treated with the highest non-toxic dose of compounds. The highly potent activity of the compounds against DENV2 infection strongly suggests their potential as a lead antiviral agent for dengue.

Matched MeSH terms: Antiviral Agents/pharmacology*
Fulltext Fragment-based in silico design of SARS-CoV-2 main protease inhibitors

Ahmad S, Usman Mirza M, Yean Kee L, Nazir M, Abdul Rahman N, Trant JF, et al.

Chem Biol Drug Des, 2021 Oct;98(4):604-619.
PMID: 34148292 DOI: 10.1111/cbdd.13914

3CLpro is essential for SARS-CoV-2 replication and infection; its inhibition using small molecules is a potential therapeutic strategy. In this study, a comprehensive crystallography-guided fragment-based drug discovery approach was employed to design new inhibitors for SARS-CoV-2 3CLpro. All small molecules co-crystallized with SARS-CoV-2 3CLpro with structures deposited in the Protein Data Bank were used as inputs. Fragments sitting in the binding pocket (87) were grouped into eight geographical types. They were interactively coupled using various synthetically reasonable linkers to generate larger molecules with divalent binding modes taking advantage of two different fragments' interactions. In total, 1,251 compounds were proposed, and 7,158 stereoisomers were screened using Glide (standard precision and extra precision), AutoDock Vina, and Prime MMGBSA. The top 22 hits having conformations approaching the linear combination of their constituent fragments were selected for MD simulation on Desmond. MD simulation suggested 15 of these did adopt conformations very close to their constituent pieces with far higher binding affinity than either constituent domain alone. These structures could provide a starting point for the further design of SARS-CoV-2 3CLpro inhibitors with improved binding, and structures are provided.

Matched MeSH terms: Antiviral Agents/pharmacology
Fulltext Rational attenuation of RNA viruses with zinc finger antiviral protein

Gonçalves-Carneiro D, Mastrocola E, Lei X, DaSilva J, Chan YF, Bieniasz PD

Nat Microbiol, 2022 Oct;7(10):1558-1567.
PMID: 36075961 DOI: 10.1038/s41564-022-01223-8

Attenuation of a virulent virus is a proven approach for generating vaccines but can be unpredictable. For example, synonymous recoding of viral genomes can attenuate replication but sometimes results in pleiotropic effects that confound rational vaccine design. To enable specific, conditional attenuation of viruses, we examined target RNA features that enable zinc finger antiviral protein (ZAP) function. ZAP recognized CpG dinucleotides and targeted CpG-rich RNAs for depletion, but RNA features such as CpG numbers, spacing and surrounding nucleotide composition that enable specific modulation by ZAP were undefined. Using synonymously mutated HIV-1 genomes, we defined several sequence features that govern ZAP sensitivity and enable stable attenuation. We applied rules derived from experiments with HIV-1 to engineer a mutant enterovirus A71 genome whose attenuation was stable and strictly ZAP-dependent, both in cell culture and in mice. The conditionally attenuated enterovirus A71 mutant elicited neutralizing antibodies that were protective against wild-type enterovirus A71 infection and disease in mice. ZAP sensitivity can thus be readily applied for the rational design of conditionally attenuated viral vaccines.

Matched MeSH terms: Antiviral Agents/pharmacology
In-vitro and in-silico anti-HSV-1 activity of a marine steroid from the jellyfish Cassiopea andromeda venom

Shamsian S, Nabipour I, Mohebbi G, Baghban N, Zare M, Zandi K, et al.

Microb Pathog, 2024 Jan;186:106486.
PMID: 38056601 DOI: 10.1016/j.micpath.2023.106486

In this study, we investigated the potential in vitro anti-HSV-1 activities of the Cassiopea andromeda jellyfish tentacle extract (TE) and its fractions, as well as computational work on the thymidine kinase (TK) inhibitory activity of the identified secondary metabolites. The LD50, secondary metabolite identification, preparative and analytical chromatography, and in silico TK assessment were performed using the Spearman-Karber, GC-MS, silica gel column chromatography, RP-HPLC, LC-MS, and docking methods, respectively. The antiviral activity of TE and the two purified compounds Ca2 and Ca7 against HSV-1 in Vero cells was evaluated by MTT and RT-PCR assays. The LD50 (IV, mouse) values of TE, Ca2, and Ca7 were 104.0 ± 4, 5120 ± 14, and 197.0 ± 7 (μg/kg), respectively. They exhibited extremely effective antiviral activity against HSV-1. The CC50 and MNTD of TE, Ca2, and Ca7 were (125, 62.5), (25, 12.5), and (50, 3.125) μg/ml, respectively. GC-MS analysis of the tentacle extract revealed seven structurally distinct chemical compositions. Four of the seven compounds had a steroid structure. According to the docking results, all compounds showed binding affinity to the active sites of both thymidine kinase chains. Among them, the steroid compound Pregn-5-ene-3,11-dione, 17,20:20,21 bis [methylenebis(oxy)]-, cyclic 3-(1,2-ethane diyl acetal) (Ca2) exhibited the highest affinity for both enzyme chains, surpassing that of standard acyclovir. In silico data confirmed the experimental results. We conclude that the oxosteroid Ca2 may act as a potent agent against HSV-1.

Matched MeSH terms: Antiviral Agents/pharmacology
Fulltext Identification of novel human USP2 inhibitor and its putative role in treatment of COVID-19 by inhibiting SARS-CoV-2 papain-like (PLpro) protease

Mirza MU, Ahmad S, Abdullah I, Froeyen M

Comput Biol Chem, 2020 Dec;89:107376.
PMID: 32979815 DOI: 10.1016/j.compbiolchem.2020.107376

Human ubiquitin carboxyl-terminal hydrolase-2 (USP2) inhibitors, such as thiopurine analogs, have been reported to inhibit SARS-CoV papain-like proteases (PLpro). The PLpro have significant functional implications in the innate immune response during SARS-CoV-2 infection and considered an important antiviral target. Both proteases share strikingly similar USP fold with right-handed thumb-palm-fingers structural scaffold and conserved catalytic triad Cys-His-Asp/Asn. In this urgency situation of COVID-19 outbreak, there is a lack of in-vitro facilities readily available to test SARS-CoV-2 inhibitors in whole-cell assays. Therefore, we adopted an alternate route to identify potential USP2 inhibitor through integrated in-silico efforts. After an extensive virtual screening protocol, the best compounds were selected and tested. The compound Z93 showed significant IC50 value against Jurkat (9.67 μM) and MOTL-4 cells (11.8 μM). The binding mode of Z93 was extensively analyzed through molecular docking, followed by MD simulations, and molecular interactions were compared with SARS-CoV-2. The relative binding poses of Z93 fitted well in the binding site of both proteases and showed consensus π-π stacking and H-bond interactions with histidine and aspartate/asparagine residues of the catalytic triad. These results led us to speculate that compound Z93 might be the first potential chemical lead against SARS-CoV-2 PLpro, which warrants in-vitro evaluations.

Matched MeSH terms: Antiviral Agents/pharmacology*
Fulltext Computational Lock and Key and Dynamic Trajectory Analysis of Natural Biophors Against COVID-19 Spike Protein to Identify Effective Lead Molecules

Navabshan I, Sakthivel B, Pandiyan R, Antoniraj MG, Dharmaraj S, Ashokkumar V, et al.

Mol Biotechnol, 2021 Oct;63(10):898-908.
PMID: 34159564 DOI: 10.1007/s12033-021-00358-z

New pandemic infection of coronaviridae family virus spread to more than 210 countries with total infection of 1,136,851 and 62,955 (4.6%) deaths until 5th April 2020. Which stopped the regular cycle of humankind but the nature is consistently running. There is no micro molecule remedy found yet to restore the regular life of people. Hence, we decided to work on natural biophores against the COVID proteins. As a first step, major phytoconstituents of antiviral herbs like Leucas aspera, Morinda citrifolia, Azadirachta indica, Curcuma longa, Piper nigrum, Ocimum tenuiflorum, and Corallium rubrum collected and performed the lock and key analysis with major spike protein of COVID-19 to find the best fitting lead biophore using computational drug design platform. The results of protocol run showed, phytoconstituents of Morinda citrifolia and Leucas aspera were found lower binding energy range of - 55.18 to - 25.34 kcal/mol, respectively and compared with Hydroxychloroquine (HCQ) (- 24.29 kcal/mol) and Remdesivir (- 25.38 kcal/mol). The results conclude that, core skeletons chromen, anthracene 9, 11 dione and long-chain alkyl acids/ester-containing biophores showen high stable antagonistic affinity with S-protein. Which leads the breakdown of spike protein and ACE2 receptor complex formation and host mechanism of corono virus. In addition, the dynamic trajectory analysis confirmed the complete denaturation of spike protein by the molecule 4-(24-hydroxy-1-oxo-5-n-propyltetracosanyl)-phenol from Leucas aspera and stability of spike-ligand complex. These biophores will aid the researcher to fabricate new promising analogue and being recommended to assess its COVID-19 treatment.

Matched MeSH terms: Antiviral Agents/pharmacology
Fulltext A cell-based screening system for anti-influenza A virus agents

Wong WY, Loh SW, Ng WL, Tan MC, Yeo KS, Looi CY, et al.

Sci Rep, 2015;5:8672.
PMID: 25728279 DOI: 10.1038/srep08672

Emerging of drug resistant influenza A virus (IAV) has been a big challenge for anti-IAV therapy. In this study, we describe a relatively easy and safe cell-based screening system for anti-IAV replication inhibitors using a non-replicative strain of IAV. A nickel (II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone (NiPT5) was recently found to exhibit anti-inflammatory activity in vivo and in vitro. NiPT5 impedes the signaling cascades that lead to the activation of NF-κB in response to different stimuli, such as LPS and TNFα. Using our cell-based screening system, we report that pretreating cells with NiPT5 protects cells from influenza A virus (IAV) and vesicular stomatitis virus (VSV) infection. Furthermore, NiPT5 inhibits replication of IAV by inhibiting transcription and translation of vRNAs of IAV. Additionally, NiPT5 reduces IAV-induced type I interferon response and cytokines production. Moreover, NiPT5 prevents activation of NF-κB, and IRF3 in response to IAV infection. These results demonstrate that NiPT5 is a potent antiviral agent that inhibits the early phase of IAV replication.

Matched MeSH terms: Antiviral Agents/pharmacology*
Fulltext Prophylactic effect of herbal-marine compound (HESA-A) on influenza A virus infectivity

Mehrbod P, Ideris A, Omar AR, Hair-Bejo M

BMC Complement Altern Med, 2014;14:131.
PMID: 24708698 DOI: 10.1186/1472-6882-14-131

Influenza virus is still a severe respiratory disease affecting human and other species. As conventional drugs are not recommended for long time because of side effects and drug resistance occurrence, traditional medication has been focused as alternative remedy. HESA-A is a natural compound from herbal-marine origin. Previous studies have reported the therapeutic properties of HESA-A on psoriasis vulgaris and different types of cancers and we also showed its anti-inflammatory effects against influenza A infection.

Matched MeSH terms: Antiviral Agents/pharmacology*

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