Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors

Perez-Lemus, Gustavo R.; Menéndez, Cintia A.; Alvarado, Walter; Byléhn, Fabian; Pablo, Juan

doi:10.1126/sciadv.abj4526

Cited by 29 publications

(25 citation statements)

References 39 publications

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“…The binding site of the SARS-COV-2 helicase (NSP13) is located between the 1A and 2A domains, comprising important amino acids necessary for ATP binding; Asp374, Glu375, Ser377, Asp401, Gln404, Arg443, Lys288, Ser289, Arg567, and Gly538 (PDB ID: 5RLG ). Experimental and in-silico studies have also been reported targeting the helicase with different molecules [ [106] , [107] , [108] , [109] , [110] , [111] ]. We docked the fortunellin into the active site of the SARS-CoV-2 helicase and found that it achieved a better docking score of −9.8 kcal/mol than the re-docked co-crystallized ligand.…”

Section: Discussionmentioning

confidence: 99%

Computational exploration of the dual role of the phytochemical fortunellin: Antiviral activities against SARS-CoV-2 and immunomodulatory abilities against the host

Agrawal

Pathak

Mishra

et al. 2022

Computers in Biology and Medicine

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Section: Discussionmentioning

confidence: 99%

Computational exploration of the dual role of the phytochemical fortunellin: Antiviral activities against SARS-CoV-2 and immunomodulatory abilities against the host

Agrawal

Pathak

Mishra

et al. 2022

Computers in Biology and Medicine

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“…It is also thought to facilitate proper folding and replication of viral RNA [ 23 ]. Inhibition of NSP13 with bismuth salts and other agents blocks viral replication [ 24 – 27 ]. In addition, NSP13 is capable of suppressing type I IFN production and signaling [ 17 – 19 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 NSP13 helicase suppresses interferon signaling by perturbing JAK1 phosphorylation of STAT1

et al. 2022

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Background SARS-CoV-2 is the causative agent of COVID-19. Overproduction and release of proinflammatory cytokines are the underlying cause of severe COVID-19. Treatment of this condition with JAK inhibitors is a double-edged sword, which might result in the suppression of proinflammatory cytokine storm and the concurrent enhancement of viral infection, since JAK signaling is essential for host antiviral response. Improving the current JAK inhibitor therapy requires a detailed molecular analysis on how SARS-CoV-2 modulates interferon (IFN)-induced activation of JAK-STAT signaling. Results In this study, we focused on the molecular mechanism by which SARS-CoV-2 NSP13 helicase suppresses IFN signaling. Expression of SARS-CoV-2 NSP13 alleviated transcriptional activity driven by type I and type II IFN-responsive enhancer elements. It also prevented nuclear translocation of STAT1 and STAT2. The suppression of NSP13 on IFN signaling occurred at the step of STAT1 phosphorylation. Nucleic acid binding-defective mutant K345A K347A and NTPase-deficient mutant E375A of NSP13 were found to have largely lost the ability to suppress IFN-β-induced STAT1 phosphorylation and transcriptional activation, indicating the requirement of the helicase activity for NSP13-mediated inhibition of STAT1 phosphorylation. NSP13 did not interact with JAK1 nor prevent STAT1-JAK1 complex formation. Mechanistically, NSP13 interacted with STAT1 to prevent JAK1 kinase from phosphorylating STAT1. Conclusion SARS-CoV-2 NSP13 helicase broadly suppresses IFN signaling by targeting JAK1 phosphorylation of STAT1.

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“…Particularly, it is invaluable for assessment of a myriad of computationally identified potential inhibitors of nsp13 from various CoVs. 36 Importantly, the discovery of the druglike small-molecule inhibitors of nsp13 we reported here will enable parallel projects by scientific communities that will accelerate discovery of potent and selective inhibitors of CoV replication and propagation.…”

Section: Discussionmentioning

confidence: 92%

Kinetic Characterization of SARS-CoV-2 nsp13 ATPase Activity and Discovery of Small-Molecule Inhibitors

et al. 2022

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SARS-CoV-2 non-structural protein 13 (nsp13) is a highly conserved helicase and RNA 5′-triphosphatase. It uses the energy derived from the hydrolysis of nucleoside triphosphates for directional movement along the nucleic acids and promotes the unwinding of double-stranded nucleic acids. Nsp13 is essential for replication and propagation of all human and non-human coronaviruses. Combined with its defined nucleotide binding site and druggability, nsp13 is one of the most promising candidates for the development of pan-coronavirus therapeutics. Here, we report the development and optimization of bioluminescence assays for kinetic characterization of nsp13 ATPase activity in the presence and absence of single-stranded DNA. Screening of a library of 5000 small molecules in the presence of single-stranded DNA resulted in the discovery of six nsp13 small-molecule inhibitors with IC 50 values ranging from 6 ± 0.5 to 50 ± 6 μM. In addition to providing validated methods for high-throughput screening of nsp13 in drug discovery campaigns, the reproducible screening hits we present here could potentially be chemistry starting points toward the development of more potent and selective nsp13 inhibitors, enabling the discovery of antiviral therapeutics.

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Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors

Abstract: Molecular dynamics simulations are used to unravel the SARS-CoV-2 NSP13 behavior in interaction with natural ligands and inhibitors.

Cited by 29 publications

References 39 publications

Computational exploration of the dual role of the phytochemical fortunellin: Antiviral activities against SARS-CoV-2 and immunomodulatory abilities against the host

Computational exploration of the dual role of the phytochemical fortunellin: Antiviral activities against SARS-CoV-2 and immunomodulatory abilities against the host

SARS-CoV-2 NSP13 helicase suppresses interferon signaling by perturbing JAK1 phosphorylation of STAT1

Kinetic Characterization of SARS-CoV-2 nsp13 ATPase Activity and Discovery of Small-Molecule Inhibitors

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