Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp13 helicase

Zeng, Jingkun; Weissmann, Florian; Bertolin, Agustina P.; Posse, Viktor; Canal, Berta; Ulferts, Rachel; Wu, Mary; Harvey, Ruth; Hussain, Saira; Milligan, Jennifer C.; Roustan, Chloë; Borg, Annabel; McCoy, Laura E; Drury, Lucy S.; Kjær, Svend; McCauley, John W.; Howell, Michael; Beale, Rupert; Diffley, John F.X.

doi:10.1042/bcj20210201

Cited by 56 publications

(57 citation statements)

References 74 publications

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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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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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“…Saquinavir, an HIV protease inhibitor used in combination with other antiretroviral agents for the treatment of HIV-1, displays an in vitro EC 50 of 8.8 µM ( Yamamoto et al, 2020 ); zafirlukast, a leukotriene receptor antagonist used for prophylaxis and chronic treatment of asthma, exhibits an in vitro SARS-CoV-2 IC 50 value of 3.6 µM ( Zeng et al, 2021 ). Zhu and coworkers also measured the SARS-CoV-2 and M pro inhibition of zafirlukast ( Zhu et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Computational Repurposing of Drugs and Natural Products Against SARS-CoV-2 Main Protease (Mpro) as Potential COVID-19 Therapies

Piplani

Singh

Petrovsky

et al. 2022

Front. Mol. Biosci.

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We urgently need to identify drugs to treat patients suffering from COVID-19 infection. Drugs rarely act at single molecular targets. Off-target effects are responsible for undesirable side effects and beneficial synergy between targets for specific illnesses. They have provided blockbuster drugs, e.g., Viagra for erectile dysfunction and Minoxidil for male pattern baldness. Existing drugs, those in clinical trials, and approved natural products constitute a rich resource of therapeutic agents that can be quickly repurposed, as they have already been assessed for safety in man. A key question is how to screen such compounds rapidly and efficiently for activity against new pandemic pathogens such as SARS-CoV-2. Here, we show how a fast and robust computational process can be used to screen large libraries of drugs and natural compounds to identify those that may inhibit the main protease of SARS-CoV-2. We show that the shortlist of 84 candidates with the strongest predicted binding affinities is highly enriched (≥25%) in compounds experimentally validated in vivo or in vitro to have activity in SARS-CoV-2. The top candidates also include drugs and natural products not previously identified as having COVID-19 activity, thereby providing leads for experimental validation. This predictive in silico screening pipeline will be valuable for repurposing existing drugs and discovering new drug candidates against other medically important pathogens relevant to future pandemics.

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“…Two compounds targeting the RdRp (remdesivir and molnupiravir) and the 3C-like protease inhibitor nirmatrelvir (sold under the name Paxlovid) are already available as human medicines. In addition, inhibitors of other coronaviral enzymes, such as the helicase [ 27 , 28 ], endo- and exonuclease [ 29 , 30 ] or the methyltransferases [ 18 , 19 , 31 ], have been actively developed. However, the goal is to develop compounds that would be active against multiple viruses or even multiple viral families.…”

Section: Discussionmentioning

confidence: 99%

A Helquat-like Compound as a Potent Inhibitor of Flaviviral and Coronaviral Polymerases

et al. 2022

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Positive-sense single-stranded RNA (+RNA) viruses have proven to be important pathogens that are able to threaten and deeply damage modern societies, as illustrated by the ongoing COVID-19 pandemic. Therefore, compounds active against most or many +RNA viruses are urgently needed. Here, we present PR673, a helquat-like compound that is able to inhibit the replication of SARS-CoV-2 and tick-borne encephalitis virus in cell culture. Using in vitro polymerase assays, we demonstrate that PR673 inhibits RNA synthesis by viral RNA-dependent RNA polymerases (RdRps). Our results illustrate that the development of broad-spectrum non-nucleoside inhibitors of RdRps is feasible.

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Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp13 helicase

Cited by 56 publications

References 74 publications

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

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

Computational Repurposing of Drugs and Natural Products Against SARS-CoV-2 Main Protease (Mpro) as Potential COVID-19 Therapies

A Helquat-like Compound as a Potent Inhibitor of Flaviviral and Coronaviral Polymerases

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