Identification of potent small molecule inhibitors of SARS-CoV-2 entry.

Autor:	Mediouni S; Scripps Research, Department of Immunology and Microbiology, Scripps Research, Jupiter, FL 33458, USA., Mou H; Scripps Research, Department of Immunology and Microbiology, Scripps Research, Jupiter, FL 33458, USA., Otsuka Y; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA., Jablonski JA; Scripps Research, Department of Immunology and Microbiology, Scripps Research, Jupiter, FL 33458, USA., Adcock RS; Center for Predictive Medicine, Department of Microbiology Immunology, School of Medicine, University of Louisville, KY 40202, USA., Batra L; Center for Predictive Medicine, Department of Microbiology Immunology, School of Medicine, University of Louisville, KY 40202, USA., Chung DH; Center for Predictive Medicine, Department of Microbiology Immunology, School of Medicine, University of Louisville, KY 40202, USA., Rood C; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA., de Vera IMS; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA., Rahaim R Jr; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA., Ullah S; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA., Yu X; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA., Getmanenko YA; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA., Kennedy NM; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA., Wang C; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA., Nguyen TT; CALIBR, Scripps Research, 11119N Torrey Pines Rd, La Jolla, CA 9203, USA., Hull M; CALIBR, Scripps Research, 11119N Torrey Pines Rd, La Jolla, CA 9203, USA., Chen E; CALIBR, Scripps Research, 11119N Torrey Pines Rd, La Jolla, CA 9203, USA., Bannister TD; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA., Baillargeon P; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA., Scampavia L; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA., Farzan M; Scripps Research, Department of Immunology and Microbiology, Scripps Research, Jupiter, FL 33458, USA., Valente ST; Scripps Research, Department of Immunology and Microbiology, Scripps Research, Jupiter, FL 33458, USA., Spicer TP; Scripps Research, Department of Molecular Medicine, Scripps Research, Jupiter, FL 33458, USA. Electronic address: spicert@scripps.edu.
Jazyk:	angličtina
Zdroj:	SLAS discovery : advancing life sciences R & D [SLAS Discov] 2022 Jan; Vol. 27 (1), pp. 8-19. Date of Electronic Publication: 2021 Oct 23.
DOI:	10.1016/j.slasd.2021.10.012
Abstrakt:	The severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 remains a persistent threat to mankind, especially for the immunocompromised and elderly for which the vaccine may have limited effectiveness. Entry of SARS-CoV-2 requires a high affinity interaction of the viral spike protein with the cellular receptor angiotensin-converting enzyme 2. Novel mutations on the spike protein correlate with the high transmissibility of new variants of SARS-CoV-2, highlighting the need for small molecule inhibitors of virus entry into target cells. We report the identification of such inhibitors through a robust high-throughput screen testing 15,000 small molecules from unique libraries. Several leads were validated in a suite of mechanistic assays, including whole cell SARS-CoV-2 infectivity assays. The main lead compound, calpeptin, was further characterized using SARS-CoV-1 and the novel SARS-CoV-2 variant entry assays, SARS-CoV-2 protease assays and molecular docking. This study reveals calpeptin as a potent and specific inhibitor of SARS-CoV-2 and some variants. Competing Interests: Declaration of Conflicting Interest The are no conflicts of interest amongst any of the authors and the work pertained in this manuscript. (Copyright © 2021. Published by Elsevier Inc.)
Databáze:	MEDLINE
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