Exploration of the P1 residue in 3CL protease inhibitors leading to the discovery of a 2-tetrahydrofuran P1 replacement.

Autor: Barton LS; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States. Electronic address: linda.s.barton@gsk.com., Callahan JF; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Cantizani J; GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain., Concha NO; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Cotillo Torrejon I; GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain., Goodwin NC; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Joshi-Pangu A; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Kiesow TJ; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., McAtee JJ; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Mellinger M; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Nixon CJ; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Padrón-Barthe L; GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain., Patterson JR; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Pearson ND; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Pouliot JJ; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Rendina AR; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Buitrago Santanilla A; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Schneck JL; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Sanz O; GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain., Thalji RK; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Ward P; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., Williams SP; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States., King BW; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Feb 15; Vol. 100, pp. 117618. Date of Electronic Publication: 2024 Jan 29.
DOI: 10.1016/j.bmc.2024.117618
Abstrakt: The virally encoded 3C-like protease (3CL pro ) is a well-validated drug target for the inhibition of coronaviruses including Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Most inhibitors of 3CL pro are peptidomimetic, with a γ-lactam in place of Gln at the P1 position of the pseudopeptide chain. An effort was pursued to identify a viable alternative to the γ-lactam P1 mimetic which would improve physicochemical properties while retaining affinity for the target. Discovery of a 2-tetrahydrofuran as a suitable P1 replacement that is a potent enzymatic inhibitor of 3CL pro in SARS-CoV-2 virus is described herein.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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