Authors:	Welker, Armin Kersten, Christian Müller, Christin Madhugiri, Ramakanth Zimmer, Collin Müller, Patrick Zimmermann, Robert Hammerschmidt, Stefan Maus, Hannah Ziebuhr, John Sotriffer, Christoph Schirmeister, Tanja
Title:	Structure-activity relationships of benzamides and isoindolines designed as SARS-CoV protease inhibitors effective against SARS-CoV-2
Online publication date:	28-Jun-2021
Year of first publication:	2021
Language:	english
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 PLpro 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 PLpro are valuable starting points for the development of new pan-coronaviral inhibitors.
DDC:	570 Biowissenschaften 570 Life sciences 610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 09 Chemie, Pharmazie u. Geowissensch.
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-6098
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	ChemMedChem 16 2
Pages or article number:	340 354
Publisher:	Wiley-VCH
Publisher place:	Weinheim u.a.
Issue date:	2021
ISSN:	1860-7187
Publisher URL:	https://doi.org/10.1002/cmdc.202000548
Publisher DOI:	10.1002/cmdc.202000548
Appears in collections:	JGU-Publikationen