scholarly journals The amyloidogenicity of the influenza virus PB1-derived peptide sheds light on its antiviral activity

2017 ◽  
Author(s):  
Yana A. Zabrodskaya ◽  
Dmitry V. Lebedev ◽  
Marja A. Egorova ◽  
Aram A. Shaldzhyan ◽  
Alexey V. Shvetsov ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Activity ◽  
Antiviral Drug ◽  
Alpha Helix ◽  
Terminal Region ◽  
Helical Conformation ◽  
Amino Acid Residues ◽  
Polymerase Complex ◽  
Low Concentrations ◽  
Promising Target

AbstractThe influenza virus polymerase complex is a promising target for new antiviral drug development. It is known that, within the influenza virus polymerase complex, the PB1 subunit region from the 1st to the 25th amino acid residues has to be is in an alpha-helical conformation for proper interaction with the PA subunit. We have previously shown that PB1(6–13) peptide at low concentrations is able to interact with the PB1 subunit N-terminal region in a peptide model which shows aggregate formation and antiviral activity in cell cultures.In this paper, it was shown that PB1(6–13) peptide is prone to form the amyloid-like fibrillar aggregates. The peptide homo-oligomerization kinetics were examined, and the affinity and characteristic interaction time of PB1(6–13) peptide monomers and the influenza virus polymerase complex PB1 subunit N-terminal region were evaluated by the SPR and TR-SAXS methods. Based on the data obtained, a hypothesis about the PB1(6–13) peptide mechanism of action was proposed: the peptide in its monomeric form is capable of altering the conformation of the PB1 subunit N-terminal region, causing a change from an alpha helix to a beta structure. This conformational change disrupts PB1 and PA subunit interaction and, by that mechanism, the peptide displays antiviral activity.Graphical abstract

scholarly journals Capsid Protein C of Tick-Borne Encephalitis Virus Tolerates Large Internal Deletions and Is a Favorable Target for Attenuation of Virulence

2002 ◽  
Vol 76 (7) ◽  
pp. 3534-3543 ◽  
Author(s):  
Regina M. Kofler ◽  
Franz X. Heinz ◽  
Christian W. Mandl
Keyword(s):  
Amino Acid ◽  
Capsid Protein ◽  
Protein C ◽  
Alpha Helix ◽  
Helical Conformation ◽  
Amino Acid Residues ◽  
Structural Class ◽  
Hydrophobic Domain ◽  
Tick Borne Encephalitis ◽  
Subviral Particles

ABSTRACT Deletions ranging in size from 4 to 21 amino acid residues were introduced into the capsid protein of the flavivirus tick-borne encephalitis (TBE) virus. These deletions incrementally affected a hydrophobic domain which is present at the center of all flavivirus capsid protein sequences and part of which may form an amphipathic alpha-helix. In the context of the full-length TBE genome, the deletions did not measurably affect protein expression and up to a deletion length of 16 amino acid residues, corresponding to almost 17% of mature protein C, viable virus was recovered. This virus was strongly attenuated but highly immunogenic in adult mice, revealing capsid protein C as a new and attractive target for the directed attenuation of flaviviruses. Apparently, the larger deletions interfered with the correct assembly of infectious virus particles, and this disturbance of virion assembly is likely to be the molecular basis of attenuation. However, all of the mutants carrying large deletions produced substantial amounts of subviral particles, which as judged from density gradient analyses were identical to recombinant subviral particles as obtained by the expression of the surface proteins prM and E alone. The structural and functional flexibility of protein C revealed in this study and its predicted largely alpha-helical conformation are reminiscent of capsid proteins of other enveloped viruses, such as alphaviruses (N-terminal domain of the capsid protein), retroviruses, and hepadnaviruses and suggest that all of these may belong to a common structural class, which is fundamentally distinct from the classical β-barrel structures of many icosahedral viral capsids. The possibility of attenuating flaviviruses by disturbing virus assembly and favoring the production of noninfectious but highly immunogenic subviral particles opens up a promising new avenue for the development of live flavivirus vaccines.

scholarly journals Synthesis and Antiviral Activity of Camphene Derivatives against Different Types of Viruses

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2235
Author(s):  
Anastasiya S. Sokolova ◽  
Valentina P. Putilova ◽  
Olga I. Yarovaya ◽  
Anastasiya V. Zybkina ◽  
Ekaterina D. Mordvinova ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Activity ◽  
Rational Design ◽  
Ebola Virus ◽  
Viral Infections ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Surface Proteins ◽  
Hantaan Virus

To date, the ‘one bug-one drug’ approach to antiviral drug development cannot effectively respond to the constant threat posed by an increasing diversity of viruses causing outbreaks of viral infections that turn out to be pathogenic for humans. Evidently, there is an urgent need for new strategies to develop efficient antiviral agents with broad-spectrum activities. In this paper, we identified camphene derivatives that showed broad antiviral activities in vitro against a panel of enveloped pathogenic viruses, including influenza virus A/PR/8/34 (H1N1), Ebola virus (EBOV), and the Hantaan virus. The lead-compound 2a, with pyrrolidine cycle in its structure, displayed antiviral activity against influenza virus (IC50 = 45.3 µM), Ebola pseudotype viruses (IC50 = 0.12 µM), and authentic EBOV (IC50 = 18.3 µM), as well as against pseudoviruses with Hantaan virus Gn-Gc glycoprotein (IC50 = 9.1 µM). The results of antiviral activity studies using pseudotype viruses and molecular modeling suggest that surface proteins of the viruses required for the fusion process between viral and cellular membranes are the likely target of compound 2a. The key structural fragments responsible for efficient binding are the bicyclic natural framework and the nitrogen atom. These data encourage us to conduct further investigations using bicyclic monoterpenoids as a scaffold for the rational design of membrane-fusion targeting inhibitors.

scholarly journals SARS-CoV-2 NSP1 C-terminal region (residues 130-180) is an intrinsically disordered region

2020 ◽  
Author(s):  
Amit Kumar ◽  
Ankur Kumar ◽  
Prateek Kumar ◽  
Neha Garg ◽  
Rajanish Giri
Keyword(s):  
Hydrophobic Interaction ◽  
Nonstructural Protein ◽  
Conformational Dynamics ◽  
Experimental Studies ◽  
Alpha Helix ◽  
Lipid Vesicles ◽  
Terminal Region ◽  
Helical Conformation ◽  
Intrinsically Disordered ◽  
Nonstructural Protein 1

AbstractNonstructural protein 1 (NSP1) of SARS-CoV-2 plays a key role in downregulation of RIG-I pathways and interacts with 40 S ribosome. Recently, the cryo-EM structure in complex with 40S ribosome is deciphered. However, the structure of full length NSP1 without any partner has not been studies. Also, the conformation of NSP1-C terminal region in isolation is not been studied. In this study, we have investigated the conformational dynamics of NSP1C-terminal region (NSP1-CTR; amino acids 130-180) in isolation and under different solvent environments. The NSP1-CTR is found to be intrinsically disordered in aqueous solution. Further, we used alpha helix inducer, trifluoroethanol, and found induction of alpha helical conformation using CD spectroscopy. Additionally, in the presence of SDS, NSP1-CTR is showing a conformational change from disordered to ordered, possibly gaining alpha helix in part. But in presence of neutral lipid DOPC, a slight change in conformation is observed. This implies the possible role of hydrophobic interaction and electrostatic interaction on the conformational changes of NSP1. The changes in structural conformation were further studied by fluorescence-based studies, which showed significant blue shift and fluorescence quenching in the presence of SDS and TFE. Lipid vesicles also showed fluorescence-based quenching. In agreement to these result, fluorescence lifetime and fluorescence anisotropy decay suggests a change in conformational dynamics. The zeta potential studies further validated that the conformational dynamics is mostly because of hydrophobic interaction. In last, these experimental studies were complemented through Molecular Dynamics (MD) simulation which have also shown a good correlation and testify our experiments. We believe that the intrinsically disordered nature of the NSP1-CTR will have implications in disorder based binding promiscuity with its interacting proteins.

scholarly journals Nitrogen-Based Heterocyclic Compounds: A Promising Class of Antiviral Agents against Chikungunya Virus

Life ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 16
Author(s):  
Andreza C. Santana ◽  
Ronaldo C. Silva Filho ◽  
José C. J. M. D. S. Menezes ◽  
Diego Allonso ◽  
Vinícius R. Campos
Keyword(s):  
Antiviral Activity ◽  
Mechanism Of Action ◽  
Heterocyclic Compounds ◽  
Chikungunya Virus ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Important Class ◽  
Available Nitrogen ◽  
Global Threat ◽  
Present Understanding

Arboviruses, in general, are a global threat due to their morbidity and mortality, which results in an important social and economic impact. Chikungunya virus (CHIKV), one of the most relevant arbovirus currently known, is a re-emergent virus that causes a disease named chikungunya fever, characterized by a severe arthralgia (joint pains) that can persist for several months or years in some individuals. Until now, no vaccine or specific antiviral drug is commercially available. Nitrogen heterocyclic scaffolds are found in medications, such as aristeromycin, favipiravir, fluorouracil, 6-azauridine, thioguanine, pyrimethamine, among others. New families of natural and synthetic nitrogen analogous compounds are reported to have significant anti-CHIKV effects. In the present work, we focus on these nitrogen-based heterocyclic compounds as an important class with CHIKV antiviral activity. We summarize the present understanding on this class of compounds against CHIKV and also present their possible mechanism of action.

scholarly journals Synthesis and Antiviral Evaluation of Nucleoside Analogues Bearing One Pyrimidine Moiety and Two D-Ribofuranosyl Residues

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3678
Author(s):  
Olga V. Andreeva ◽  
Bulat F. Garifullin ◽  
Vladimir V. Zarubaev ◽  
Alexander V. Slita ◽  
Iana L. Yesaulkova ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Activity ◽  
Theoretical Calculations ◽  
Nucleoside Analogs ◽  
Coxsackievirus B3 ◽  
Nucleoside Analogues ◽  
Moderate Activity ◽  
Coat Proteins ◽  
Influenza Virus A ◽  
Ic50 Values

A series of 1,2,3-triazolyl nucleoside analogues in which 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via polymethylene linkers to both nitrogen atoms of the heterocycle moiety (uracil, 6-methyluracil, thymine, quinazoline-2,4-dione, alloxazine) or to the C-5 and N-3 atoms of the 6-methyluracil moiety was synthesized. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. Antiviral assays revealed three compounds, 2i, 5i, 11c, which showed moderate activity against influenza virus A H1N1 with IC50 values of 57.5 µM, 24.3 µM, and 29.2 µM, respectively. In the first two nucleoside analogues, 1,2,3-triazol-4-yl-β-d-ribofuranosyl fragments are attached via butylene linkers to N-1 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine, respectively). In nucleoside analogue 11c, two 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached via propylene linkers to the C-5 and N-3 atoms of the 6-methyluracil moiety. Almost all synthesized 1,2,3-triazolyl nucleoside analogues showed no antiviral activity against the coxsackie B3 virus. Two exceptions are 1,2,3-triazolyl nucleoside analogs 2f and 5f, in which 1,2,3-triazol-4-yl-2′,3′,5′-tri-O-acetyl-β-d-ribofuranose fragments are attached to the C-5 and N-3 atoms of the heterocycle moiety (6-methyluracil and alloxazine respectively). These compounds exhibited high antiviral potency against the coxsackie B3 virus with IC50 values of 12.4 and 11.3 µM, respectively, although both were inactive against influenza virus A H1N1. According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 2i, 5i, and 11c against the H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRp). As to the antiviral activity of nucleoside analogs 2f and 5f against coxsackievirus B3, it can be explained by their interaction with the coat proteins VP1 and VP2.

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