Journal article

Publication year: 2021

Pages: 340-354

Journal: ChemMedChem

Volume number: 16

Issue number: 2

ISSN: 1860-7179

eISSN: 1860-7187

Open access status: Hybrid

DOI Link: https://doi.org/10.1002/cmdc.202000548

Publisher: Wiley

Abstract: 
Inhibition of coronavirus (CoV)-encoded papain-like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure-activity relationships (SAR) of the noncovalent active-site directed inhibitor (R)-5-amino-2-methyl-N-(1-(naphthalen-1-yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS-CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PL(pro)inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS-CoV-2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS-CoV PL(pro)are valuable starting points for the development of new pan-coronaviral inhibitors.

Harvard Citation style: Welker, A., Kersten, C., Mueller, C., Madhugiri, R., Zimmer, C., Mueller, P., et al. (2021) Deal;Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2, ChemMedChem, 16(2), pp. 340-354. https://doi.org/10.1002/cmdc.202000548

APA Citation style: Welker, A., Kersten, C., Mueller, C., Madhugiri, R., Zimmer, C., Mueller, P., Zimmermann, R., Hammerschmidt, S., Maus, H., Ziebuhr, J., Sotriffer, C., & Schirmeister, T. (2021). Deal;Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2. ChemMedChem. 16(2), 340-354. https://doi.org/10.1002/cmdc.202000548