Peptide inhibitors derived from the nsp7 and nsp8 cofactors of nsp12 targeting different substrate binding sites of nsp12 of the SARS-CoV-2

Jena, N. R.; Pant, Suyash

doi:10.1080/07391102.2023.2235012

Journal of Biomolecular Structure and Dynamics

2023

DOI: 10.1080/07391102.2023.2235012

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Peptide inhibitors derived from the nsp7 and nsp8 cofactors of nsp12 targeting different substrate binding sites of nsp12 of the SARS-CoV-2

N. R. Jena

Suyash Pant

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2024

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Biochemical characterization of naturally occurring mutations in SARS‐CoV‐2 RNA‐dependent RNA polymerase

Danda,

Klimešová,

Kušková

et al. 2024

Protein Science

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Since the emergence of SARS‐CoV‐2, mutations in all subunits of the RNA‐dependent RNA polymerase (RdRp) of the virus have been repeatedly reported. Although RdRp represents a primary target for antiviral drugs, experimental studies exploring the phenotypic effect of these mutations have been limited. This study focuses on the phenotypic effects of substitutions in the three RdRp subunits: nsp7, nsp8, and nsp12, selected based on their occurrence rate and potential impact. We employed nano‐differential scanning fluorimetry and microscale thermophoresis to examine the impact of these mutations on protein stability and RdRp complex assembly. We observed diverse impacts; notably, a single mutation in nsp8 significantly increased its stability as evidenced by a 13°C increase in melting temperature, whereas certain mutations in nsp7 and nsp8 reduced their binding affinity to nsp12 during RdRp complex formation. Using a fluorometric enzymatic assay, we assessed the overall effect on RNA polymerase activity. We found that most of the examined mutations altered the polymerase activity, often as a direct result of changes in stability or affinity to the other components of the RdRp complex. Intriguingly, a combination of nsp8 A21V and nsp12 P323L mutations resulted in a 50% increase in polymerase activity. To our knowledge, this is the first biochemical study to demonstrate the impact of amino acid mutations across all components constituting the RdRp complex in emerging SARS‐CoV‐2 subvariants.

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Biochemical characterization of naturally occurring mutations in SARS‐CoV‐2 RNA‐dependent RNA polymerase

Danda,

Klimešová,

Kušková

et al. 2024

Protein Science

View full text Add to dashboard Cite

show abstract

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Peptide inhibitors derived from the nsp7 and nsp8 cofactors of nsp12 targeting different substrate binding sites of nsp12 of the SARS-CoV-2

Cited by 1 publication

References 40 publications

Biochemical characterization of naturally occurring mutations in SARS‐CoV‐2 RNA‐dependent RNA polymerase

Biochemical characterization of naturally occurring mutations in SARS‐CoV‐2 RNA‐dependent RNA polymerase

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