Non-structural protein 5 (NS5) as a target for antiviral development against established and emergent flaviviruses

Fernandes, Philipe Oliveira; Chagas, Marcelo A.; Rocha, Willian R.; Moraes, Adolfo H.

doi:10.1016/j.coviro.2021.07.001

Cited by 10 publications

(8 citation statements)

References 60 publications

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“…These 3 proteins are NS3, 59 , 60 NS4A, 61 and NS5. 62 NS3 protein performs multiple essential functions, particularly the helicase and protease activity required for genome replication; 21 , 59 NS4A maintains the integrity of the membrane and forms a replication complex component. 63 In contrast, NS5 protein conducts the methyltransferase and RNA-dependent RNA polymerase activity (RdRp).…”

Section: Resultsmentioning

confidence: 99%

S-Adenosyl-l-Homocysteine Exhibits Potential Antiviral Activity Against Dengue Virus Serotype-3 (DENV-3) in Bangladesh: A Viroinformatics-Based Approach

Shill

Jahan

Alam

et al. 2023

Bioinform Biol Insights

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Dengue outbreak is one of the concerning issues in Bangladesh due to the annual outbreak with the alarming number of death and infection. However, there is no effective antiviral drug available to treat dengue-infected patients. This study evaluated and screened antiviral drug candidates against dengue virus serotype 3 (DENV-3) through viroinformatics-based analyses. Since 2017, DENV-3 has been the predominant serotype in Bangladesh. We selected 3 non-structural proteins of DENV-3, named NS3, NS4A, and NS5, as antiviral targets. Protein modeling and validation were performed with VERIFY-3D, Ramachandran plotting, MolProbity, and PROCHECK. We found 4 drug-like compounds from DRUGBANK that can interact with these non-structural proteins of DENV-3. Then, the ADMET profile of these compounds was determined by admetSAR2, and molecular docking was performed with AutoDock, SWISSDOCK, PatchDock, and FireDock. Furthermore, they were subjected to molecular dynamics (MD) simulation study using the DESMOND module of MAESTRO academic version 2021-4 (force field OPLS_2005) to determine their solution’s stability in a predefined body environment. Two drug-like compounds named Guanosine-5’-Triphosphate (DB04137) and S-adenosyl-l-homocysteine (DB01752) were found to have an effective binding with these 3 proteins (binding energy > 33.47 KJ/mole). We found NS5 protein was stable and equilibrated in a 100 ns simulation run along with a negligible (<3Å) root-mean-square fluctuation value. The root-mean-square deviation value of the S-adenosyl-l-homocysteine-NS5 complex was less than 3Å, indicating stable binding between them. The global binding energy of S-adenosyl-l-homocysteine with NS5 was −40.52 KJ/mole as ∆G. Moreover, these 2 compounds mentioned above are non-carcinogenic according to their ADMET (chemical absorption, distribution, metabolism, excretion, and toxicity) profile (in silico). These outcomes suggest the suitability of S-adenosyl-l-homocysteine as a potential drug candidate for dengue drug discovery research.

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Section: Resultsmentioning

confidence: 99%

S-Adenosyl-l-Homocysteine Exhibits Potential Antiviral Activity Against Dengue Virus Serotype-3 (DENV-3) in Bangladesh: A Viroinformatics-Based Approach

Shill

Jahan

Alam

et al. 2023

Bioinform Biol Insights

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“…Absence of proof-reading exonuclease activity in RdRps may lead to the incorporation of mutations, and consequently, selection of variants of viruses (19). Hence, RdRp of NS5 plays a crucial role in viral genome replication and therefore, can serve as a potential anti-viral drug target (20). In fact, nucleoside and nonnucleoside inhibitors against NS5 RdRp from different viruses belonging to the flaviviridae family has been identified (21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Sofosbuvir and its tri-phosphate metabolite inhibit the RNA-dependent RNA polymerase activity of non-Structural protein 5 from the Kyasanur forest disease virus

Malik

Vijayan

Jagannath

et al. 2022

Preprint

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Kyasanur forest disease is a neglected zoonotic disease caused by a single stranded RNA based flavivirus, the incidence of which, was first recorded in 1957, in the Southern part of India. Kyasanur forest disease virus is transmitted to monkeys and humans, through the infected tick bite of Haemophysalis spinigera. Kyasanur forest disease is a febrile illness, which in severe cases, results in neurological manifestations leading to mortality. The current treatment regimens are symptomatic and supportive in nature. There are no targeted therapies available for this disease. In this study, we evaluated the ability of the FDA approved drug, Sofosbuvir to inhibit the RNA dependent RNA polymerase activity of NS5 protein from Kyasanur forest disease virus. NS5 protein containing the N-terminal methyl transferase domain and C-terminal RNA dependent RNA polymerase domain was expressed in Escherichia coli and RNA dependent RNA polymerase activity, demonstrated with the purified protein. The RNA dependent RNA polymerase assay conditions were optimized, followed by determination of apparent Km,ATP. IC50 of Sofosbuvir against RNA dependent RNA polymerase activity was determined under the optimized conditions with the purified NS5 protein. Drug repurposing strategies can accelerate the development of targeted therapies for Kyasanur forest disease. This is the first demonstration of inhibition of RNA dependent RNA polymerase activity of Kyasanur forest disease virus with a small molecule inhibitor.

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“…The authors and their published researchers have reviewed technological and methodological advances on viral structure and expression in this current issue. The most advanced experimental techniques used to characterize virus particles and virus proteins, including cryogenic electronic microscopy and nuclear magnetic resonance, were thoroughly reviewed [ 1 , 2 ]; new developments in molecular dynamics simulation and other computational strategies to study virus structure and proteins were also described [ 3 ]; an elegant integrative approach combining experimental and computational methods to characterize at atomic-level the structures and dynamics of HIV-1 capsids were carefully shown [ 4 ]; pivotal examples of the structure and functional characterization of important targets for antiviral development against SARS-CoV 2 and flaviviruses were described [ 5 , 6 , 7 ]. Also, discoveries on giant viruses, which have recently shaken the virology community, were aborded, and revisions on important viral protein drug targets were made [ 8 , 9 ].…”

mentioning

confidence: 99%

“…The contributions of Hillen [ 5 ], da Poian et al [ 7 ], and Moraes et al [ 6 ] exemplified the considerable impact the structural virology is providing to fight global-impacting viruses: the SARS-CoV 2, the HIV-1, and flaviviruses. Hillen [ 5 ] reviewed the structure and function of SARS-CoV 2 polymerase, one of the most promising drug targets against SARS-CoV 2, and organized an overview of current coronavirus RdRp structures, together with many functional studies; Da Poian et al [ 7 ] reviewed the structure and function of flaviviruses’ capsid proteins that interact with viral RNA to form the flaviviruses nucleocapsid.…”

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confidence: 99%

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Editorial overview: Special issue on virus structure and expression in current opinion in virology

Moraes

Fonseca

2022

Current Opinion in Virology

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Non-structural protein 5 (NS5) as a target for antiviral development against established and emergent flaviviruses

Cited by 10 publications

References 60 publications

S-Adenosyl-l-Homocysteine Exhibits Potential Antiviral Activity Against Dengue Virus Serotype-3 (DENV-3) in Bangladesh: A Viroinformatics-Based Approach

S-Adenosyl-l-Homocysteine Exhibits Potential Antiviral Activity Against Dengue Virus Serotype-3 (DENV-3) in Bangladesh: A Viroinformatics-Based Approach

Sofosbuvir and its tri-phosphate metabolite inhibit the RNA-dependent RNA polymerase activity of non-Structural protein 5 from the Kyasanur forest disease virus

Editorial overview: Special issue on virus structure and expression in current opinion in virology

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