Discovery of a Druggable, Cryptic Pocket in SARS-CoV-2 nsp16 Using Allosteric Inhibitors.

Autor:	Inniss NL; Department of Microbiology-Immunology and Center for Structural Biology of Infectious Diseases, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, United States., Kozic J; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, 160 00, Czech Republic., Li F; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada., Rosas-Lemus M; Department of Microbiology-Immunology and Center for Structural Biology of Infectious Diseases, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, United States., Minasov G; Department of Microbiology-Immunology and Center for Structural Biology of Infectious Diseases, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, United States., Rybáček J; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, 160 00, Czech Republic., Zhu Y; WuXi AppTec Co., Ltd, China (Shanghai) Pilot Free Trade Zone, Shanghai, 201308, China., Pohl R; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, 160 00, Czech Republic., Shuvalova L; Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, United States., Rulíšek L; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, 160 00, Czech Republic., Brunzelle JS; Northwestern Synchrotron Research Center, Life Sciences Collaborative Access Team, Northwestern University, Argonne, Illinois 60439, United States., Bednárová L; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, 160 00, Czech Republic., Štefek M; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, 160 00, Czech Republic., Kormaník JM; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, 160 00, Czech Republic., Andris E; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, 160 00, Czech Republic., Šebestík J; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, 160 00, Czech Republic., Li ASM; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada., Brown PJ; Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada., Schmitz U; Structural Chemistry, Gilead Pharmaceuticals, San Mateo, California 94404, United States., Saikatendu K; Takeda Development Center Americas, Inc., San Diego, California 92121, United States., Chang E; Takeda Development Center Americas, Inc., San Diego, California 92121, United States., Nencka R; Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague 6, 160 00, Czech Republic., Vedadi M; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada., Satchell KJF; Department of Microbiology-Immunology and Center for Structural Biology of Infectious Diseases, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, United States.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2023 Oct 13; Vol. 9 (10), pp. 1918-1931. Date of Electronic Publication: 2023 Sep 20.
DOI:	10.1021/acsinfecdis.3c00203
Abstrakt:	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.
Databáze:	MEDLINE
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