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Discovery of a Druggable, Cryptic Pocket in SARS-CoV-2 nsp16 Using Allosteric Inhibitors
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SYSNO ASEP 0576137 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Discovery of a Druggable, Cryptic Pocket in SARS-CoV-2 nsp16 Using Allosteric Inhibitors Author(s) Inniss, N. L. (US)
Kozic, Ján (UOCHB-X) ORCID
Li, F. (CA)
Rosas-Lemus, M. (US)
Minasov, G. (US)
Rybáček, Jiří (UOCHB-X) RID, ORCID
Zhu, Y. (CN)
Pohl, Radek (UOCHB-X) RID, ORCID
Shuvalova, L. (AE)
Rulíšek, Lubomír (UOCHB-X) RID, ORCID
Brunzelle, J. S. (US)
Bednárová, Lucie (UOCHB-X) RID, ORCID
Štefek, Milan (UOCHB-X)
Kormaník, Ján Michael (UOCHB-X)
Andris, Erik (UOCHB-X) ORCID
Šebestík, Jaroslav (UOCHB-X) RID, ORCID
Li, A. S. M. (CA)
Brown, P. J. (CA)
Schmitz, U. (AE)
Saikatendu, K. (US)
Chang, E. (US)
Nencka, Radim (UOCHB-X) RID, ORCID
Vedadi, M. (CA)
Satchell, K. J. F. (US)Source Title ACS Infectious Diseases. - : American Chemical Society - ISSN 2373-8227
Roč. 9, č. 10 (2023), s. 1918-1931Number of pages 14 s. Language eng - English Country US - United States Keywords coronavirus ; NSP16 methyltransferase ; covalent inhibitors ; structural biology ; antiviral OECD category Virology R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) NU20-05-00472 GA MZd - Ministry of Health (MZ) Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 001067624100001 EID SCOPUS 85174689302 DOI 10.1021/acsinfecdis.3c00203 Annotation A collaborative, open-science team undertook discovery of novel small molecule inhibitors of the SARS-CoV-2 nsp16-nsp10 2′-O-methyltransferase using a high throughput screening approach with the potential to reveal new inhibition strategies. This screen yielded compound 5a, a ligand possessing an electron-deficient double bond, as an inhibitor of SARS-CoV-2 nsp16 activity. Surprisingly, X-ray crystal structures revealed that 5a covalently binds within a previously unrecognized cryptic pocket near the S-adenosylmethionine binding cleft in a manner that prevents occupation by S-adenosylmethionine. Using a multidisciplinary approach, we examined the mechanism of binding of compound 5a to the nsp16 cryptic pocket and developed 5a derivatives that inhibited nsp16 activity and murine hepatitis virus replication in rat lung epithelial cells but proved cytotoxic to cell lines canonically used to examine SARS-CoV-2 infection. Our study reveals the druggability of this newly discovered SARS-CoV-2 nsp16 cryptic pocket, provides novel tool compounds to explore the site, and suggests a new approach for discovery of nsp16 inhibition-based pan-coronavirus therapeutics through structure-guided drug design. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2024 Electronic address https://doi.org/10.1021/acsinfecdis.3c00203
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