Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 M pro from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants.

Autor:	Wang X; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., Gotchev D; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., Fan KY; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., Vega MM; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., Mani N; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., McGovern-Gooch K; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., Cuconati A; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., Tercero B; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., Wang X; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., Carpino P; X-Chem Inc., 4800 Rue Levy Suite 200, Montreal, QC CA H4R 2P7, Canada., Maskos K; Proteros Biostructures GmbH, Bunsenstraße 7a, Martinsried, Bavaria 82152, Germany., Centrella PA; X-Chem Inc., 100 Beaver Street Suite 101, Waltham, Massachusetts 02453, United States., Schmitt A; Proteros Biostructures GmbH, Bunsenstraße 7a, Martinsried, Bavaria 82152, Germany., Preuss F; Proteros Biostructures GmbH, Bunsenstraße 7a, Martinsried, Bavaria 82152, Germany., Prasad A; Proteros Biostructures GmbH, Bunsenstraße 7a, Martinsried, Bavaria 82152, Germany., Chen CY; Proteros Biostructures GmbH, Bunsenstraße 7a, Martinsried, Bavaria 82152, Germany., Clark MA; X-Chem Inc., 100 Beaver Street Suite 101, Waltham, Massachusetts 02453, United States., Guilinger JP; X-Chem Inc., 100 Beaver Street Suite 101, Waltham, Massachusetts 02453, United States., Johnstone S; X-Chem Inc., 4800 Rue Levy Suite 200, Montreal, QC CA H4R 2P7, Canada., von König K; Proteros Biostructures GmbH, Bunsenstraße 7a, Martinsried, Bavaria 82152, Germany., Keefe AD; X-Chem Inc., 100 Beaver Street Suite 101, Waltham, Massachusetts 02453, United States., Liu J; X-Chem Inc., 100 Beaver Street Suite 101, Waltham, Massachusetts 02453, United States., Turcotte S; X-Chem Inc., 4800 Rue Levy Suite 200, Montreal, QC CA H4R 2P7, Canada., Zhang Y; X-Chem Inc., 100 Beaver Street Suite 101, Waltham, Massachusetts 02453, United States., Konz Makino DL; Proteros Biostructures GmbH, Bunsenstraße 7a, Martinsried, Bavaria 82152, Germany., Lam AM; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., Cole AG; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States., Sofia MJ; Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Nov 14; Vol. 67 (21), pp. 19623-19667. Date of Electronic Publication: 2024 Oct 25.
DOI:	10.1021/acs.jmedchem.4c02009
Abstrakt:	The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. The main protease (M pro ) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent M pro inhibitor was the first such approved therapy. Although M pro inhibitors of various chemical classes have been reported, they are generally less active against nirmatrelvir-resistant variants and have limited pan-coronavirus potential, presenting a significant human health risk upon future outbreaks. We here present a novel approach and utilized DNA-encoded chemical library screening to identify the noncovalent M pro inhibitor 5 , which demonstrated a distinct binding mode to nirmatrelvir. A macrocyclization strategy designed to lock the active conformation resulted in lactone 12 with significantly improved antiviral activity. Further optimization led to the potent lactam 26 , which demonstrated exceptional potency against nirmatrelvir-resistant variants as well as against a panel of viral main proteases from other coronaviruses.
Databáze:	MEDLINE
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