Potent Antiviral Inhibitors Research Articles

Mining Druggable Sites in Influenza A Hemagglutinin: Binding of the Pinanamine-Based Inhibitor M090.

Assessing the binding mode of drug-like compounds is key in structure-based drug design. However, this may be challenged by factors such as the structural flexibility of the target protein. In this case, state-of-the-art computational methods can be valuable to explore the linkages between structural and pharmacological data. Following this strategy, extended molecular dynamics simulations and thermodynamic integration calculations are used to examine the binding of the potent antiviral inhibitor M090 and related pinanamine-based analogues, covering a 250-fold difference in inhibitory potency to the influenza A hemagglutinin, which is essential for virus entry and membrane fusion. This analysis has disclosed the hydrophobic shielding effect played by the 3-cyclopropylthiophene moiety in M090. Furthermore, the results support the negative effect of the resistance-induced E742 → D mutation, which should weaken the binding by increasing the structural flexibility of the L2-BS loop. The results pave the way to exploration of the antiviral activity of novel compounds.

Do Ganoderma Species Represent Novel Sources of Phenolic Based Antimicrobial Agents?

Ganoderma species have been recognized as potential antimicrobial (AM) agents and have been used in traditional Chinese medicine (TCM) for a long time. The aim of this study is to examine the AM potential of autochthonous Ganoderma species (G. applanatum, G. lucidum, G. pfeifferi and G. resinaceum) from Serbia. The extraction of fungal material was prepared in different solvents (ethanol-EtOH, water-H2O, chloroform-CHCl3). Antibacterial activity (ABA) was determined using disk-diffusion, agar-well diffusion, and micro-dilution method, while for antifungal properties disk-diffusion and pour plate method were applied. Antiviral activity was tested on model DNA virus LK3 and determined by plaque assay. Statistical PCA analysis was applied for detection of correlation effects of phenolics and AM activities, while LC-MS/MS was performed for phenolics quantification. G. resinaceum CHCl3 extract expressed the most potent ABA against P. aeruginosa (MIC = 6.25 mg/mL), probably due to presence of flavonoids and 2,5-dihydroxybenzoic acid. Among H2O extracts, the highest ABA was determined for G. pfeifferi against both E. coli and S. aureus (21 and 19 mm, respectively). EtOH extracts of G. pfeifferi and G. resinaceum were the most effective against A. niger (23.8 and 20.15 mm, respectively), with special impact of phenolic acids and flavonoid isorhamnetin, while C. albicans showed the lowest susceptibility. The most potent antiviral inhibitor was G. lucidum (70.73% growth inhibition) due to the high amount of phenolic acids. To the best of our knowledge, this is the first report of a methodical AM profile of G. pfeifferi and G. resinaceum from the Balkan region including PCA analysis.

Structure of the HRV-C 3C-Rupintrivir Complex Provides New Insights for Inhibitor Design

Human rhinoviruses (HRVs) are the predominant infectious agents for the common cold worldwide. The HRV-C species cause severe illnesses in children and are closely related to acute exacerbations of asthma. 3C protease, a highly conserved enzyme, cleaves the viral polyprotein during replication and assists the virus in escaping the host immune system. These key roles make 3C protease an important drug target. A few structures of 3Cs complexed with an irreversible inhibitor rupintrivir have been determined. These structures shed light on the determinants of drug specificity. Here we describe the structures of HRV-C15 3C in free and inhibitor-bound forms. The volume-decreased S1' subsite and half-closed S2 subsite, which were thought to be unique features of enterovirus A 3C proteases, appear in the HRV-C 3C protease. Rupintrivir assumes an "intermediate" conformation in the complex, which might open up additional avenues for the design of potent antiviral inhibitors. Analysis of the features of the three-dimensional structures and the amino acid sequences of 3C proteases suggest new applications for existing drugs.

An Overview on Zika Virus and the Importance of Computational Drug Discovery

Since the beginning of the century, viral infection has become a widespread problem to public health globally. Recently, the latest newcomer of the Flaviviridae family, the Zika virus, has emerged as a potential global threat to human health. Due to lack of sufficient data at present, Zika infection has become a major cause of Zika fever, central nervous system malformations such as microcephaly, severe neuroimmunopathology, fetal abnormalities, and recently Guillain-Barre syndrome. The lack of genomic as well as proteomic information keeps the Zika virus under examination by a multitude of researchers. The rapid increase in Zika viral infections has been classified as a public health emergency by the World Health Organization. Neither preventive antiviral drugs nor effective vaccines are available on the market for combating Zika infection. Urgent innovative research is necessary to facilitate the development of protective and fruitful therapeutic agents, to improve lifespan of individuals throughout the world. Thus, we present this review to summarize the current research findings for Zika viral infection and to highlight the importance of computational drug discovery in the development of potent antiviral inhibitors against the Zika virus. We also anticipate that the information in this review will present a valuable opportunity for the prediction of efficient novel therapeutic remedies for controlling Zika.

Synthesis of multivalent difluorinated zanamivir analogs as potent antiviral inhibitors

An efficient synthesis of mono-, di-, tetra-, and octa-valent difluorinated zanamivir analogs as potent inhibitors of influenza virus is reported. The mono difluorinated zanamivir with an azide linker attached at the C-7 position was synthesized in good yield from sialic acid using Selectfluor® and (diethylaminosulfur trifluoride) DAST as the fluorination reagent. This key intermediate was attached on various alkynlated scaffolds via “Click Chemistry” to afford multivalent glycoclusters. A neuraminidase inhibition assay was used to evaluate the compounds for their inhibitory activity using H7N9 virus like particle. These multivalent sialosides show enhanced inhibition with IC50 values ∼100-fold better than the monomer indicative of the strength of using a multivalent approach.

The Pneumovirinae fusion (F) protein: A common target for vaccines and antivirals

The Pneumovirinae fusion (F) protein mediates fusion of the virus and cell membrane, an essential step for entry of the viral genome in the cell cytoplasm and initiation of a new infectious cycle. Accordingly, potent inhibitors of virus infectivity have been found among antibodies and chemical compounds that target the Pneumovirinae F protein. Recent developments in structure-based vaccines have led to a deeper understanding of F protein antigenicity, unveiling new conformations and epitopes which should assist in development of efficacious vaccines. Similarly, structure-based studies of potent antiviral inhibitors have provided information about their mode of action and mechanisms of resistance. The advantages and disadvantages of the different options to battle against important pathogens, such as human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are summarized and critically discussed in this review.

Virtual Screening and Pharmacophore Analysis of Potent Antiviral Inhibitors for Viral Proteins from Ebola virus

Virtual Screening and Pharmacophore Analysis of Potent Antiviral Inhibitors for Viral Proteins from Ebola virus Ebola hemorrhagic fever (Ebola HF) is a severe, often-fatal and one of the most virulent disease in primates. In our studies we had aimed to developed novel and potent inhibitor by targeting the VP40 and VP35 protein of the Ebola virus. These proteins are very helpful in virus replication so these are the main drug targets to prevent viral infection Protein sequence of VP40 and VP35 protein from Ebola virus ware retrieved from NCBI with Accession number NP_066245 and NP_066244 respectively and it 3D model ware predicated by using comparative homology modeling program MODELLER 9.10. The templates of VP40 and VP35 for homology modeling were downloaded from protein databank. Models evolution and validation was done by using PROCHECK with Ramachandran plot analysis. In addition we investigated that the antiviral compound bound at the cavity of model. In these studies we investigated interaction behavioral studies of antiviral compound with the modeled proteins after the analysis we select four potent antiviral compound (Famciclovir, Entecvir, Ganciclovir, Oseltamivir) for VP40 and two compound (Navirapine, Valganciclovir) for the VP35.

Insight into the Oseltamivir Resistance R292K Mutation in H5N1 Influenza Virus: A Molecular Docking and Molecular Dynamics Approach

H5N1 is a subtype of the influenza A virus that can cause disease in humans and many other animal species. Oseltamivir (Tamiflu) is a potent and selective antiviral drug employed to fight the flu virus in infected individuals by inhibiting neuraminidase (NA), a flu protein responsible for the release and spread of the progeny virions. However, oseltamivir resistance has become a critical problem. In particular, influenza strains with a R292K NA mutation are highly resistant to the oseltamivir. Though the biological functions of the mutations have previously been characterized, the structural basis behind the reduced catalytic activity and reduced protein level is not clear. In this study, molecular docking and molecular dynamics (MD) approach were employed to investigate the structural and dynamical effects throughout the protein structure and specifically, at the drug-binding pocket. Furthermore, potential of mean force was analyzed using explicit solvent MD simulations with the umbrella sampling method to explore the free energy of binding. It is believed that this study provides valuable guidance for the resistance management of oseltamivir and designing of more potent antiviral inhibitor.

Novel P2 Tris-tetrahydrofuran Group in Antiviral Compound1(GRL-0519) Fills the S2 Binding Pocket of Selected Mutants of HIV-1 Protease

GRL-0519 (1) is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resolution X-ray crystal structures of inhibitor 1 in complexes with single substitution mutants PR(R8Q), PR(D30N), PR(I50V), PR(I54M), and PR(V82A) were analyzed in relation to kinetic data. The smaller valine side chain in PR(I50V) eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PR(D30N) showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6-7-fold lower inhibition. Gln8 in PR(R8Q) replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus.

Recent Advances in Antiviral Activity of Benzo/Heterothiadiazine Dioxide Derivatives

Benzo/heterothiadiazine dioxides have been identified as important fused heterocyclic systems possessing a broad spectrum of biological activities and potential pharmacological applications. Recently, a large number of structurally novel compounds derived from these heterocycle scaffolds were identified as antiviral agents. Especially, substituted benzo/heterothiadiazine dioxide derivatives have been shown to inhibit the replication of HCMV, VZV, HCV and HIV. Of particular interest, some potent HCV polymerase inhibitors possess a benzothiadiazine dioxide scaffold, which is critical for the anti-HCV potency through strong hydrogen bond formation of the SO(2)NH group with the active site of the enzyme, as shown by X-ray crystallography. Also, some compounds belonging to the benzothiadiazine dioxide class have been found to be potent antiviral agents against HCMV and VZV. Moreover, some novel heterothiadiazine dioxide derivatives have been synthesized and evaluated as potential HIV inhibitors with lower toxicity and/or increased activity against drug-resistant virus strains. No systematic review is available in the literature on these thiadiazine derivatives in the design of potent antiviral inhibitors. In this article, we review the recent advances in the antiviral profile of this kind of compounds, as well as the impact of structural modifications and the structure-activity relationship (SAR).