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Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2.
Welker, Armin; Kersten, Christian; Müller, Christin; Madhugiri, Ramakanth; Zimmer, Collin; Müller, Patrick; Zimmermann, Robert; Hammerschmidt, Stefan; Maus, Hannah; Ziebuhr, John; Sotriffer, Christoph; Schirmeister, Tanja.
  • Welker A; Institute for Pharmacy and Food Chemistry, Justus Maximilians University Würzburg, Am Hubland, 97074, Würzburg, Germany.
  • Kersten C; Institute for Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
  • Müller C; Institute of Medical Virology, Justus Liebig University Giessen, Schubertstrasse 81, 35392, Giessen, Germany.
  • Madhugiri R; Institute of Medical Virology, Justus Liebig University Giessen, Schubertstrasse 81, 35392, Giessen, Germany.
  • Zimmer C; Institute for Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
  • Müller P; Institute for Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
  • Zimmermann R; Institute for Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
  • Hammerschmidt S; Institute for Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
  • Maus H; Institute for Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
  • Ziebuhr J; Institute of Medical Virology, Justus Liebig University Giessen, Schubertstrasse 81, 35392, Giessen, Germany.
  • Sotriffer C; Institute for Pharmacy and Food Chemistry, Justus Maximilians University Würzburg, Am Hubland, 97074, Würzburg, Germany.
  • Schirmeister T; Institute for Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Staudingerweg 5, 55128, Mainz, Germany.
ChemMedChem ; 16(2): 340-354, 2021 01 19.
Article in English | MEDLINE | ID: covidwho-878190
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Benzamides / Cysteine Proteinase Inhibitors / Isoindoles / Coronavirus 3C Proteases / SARS-CoV-2 Limits: Animals Language: English Journal: ChemMedChem Journal subject: Pharmacology / Chemistry Year: 2021 Document Type: Article Affiliation country: Cmdc.202000548

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Benzamides / Cysteine Proteinase Inhibitors / Isoindoles / Coronavirus 3C Proteases / SARS-CoV-2 Limits: Animals Language: English Journal: ChemMedChem Journal subject: Pharmacology / Chemistry Year: 2021 Document Type: Article Affiliation country: Cmdc.202000548