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Targeting the Main Protease of SARS-CoV-2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors.
Breidenbach, Julian; Lemke, Carina; Pillaiyar, Thanigaimalai; Schäkel, Laura; Al Hamwi, Ghazl; Diett, Miriam; Gedschold, Robin; Geiger, Nina; Lopez, Vittoria; Mirza, Salahuddin; Namasivayam, Vigneshwaran; Schiedel, Anke C; Sylvester, Katharina; Thimm, Dominik; Vielmuth, Christin; Phuong Vu, Lan; Zyulina, Maria; Bodem, Jochen; Gütschow, Michael; Müller, Christa E.
  • Breidenbach J; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Lemke C; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Pillaiyar T; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Schäkel L; Present address: Pharmaceutical Institute, Pharmaceutical Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
  • Al Hamwi G; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Diett M; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Gedschold R; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Geiger N; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Lopez V; Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Versbacher Strasse 7, 97078, Würzburg, Germany.
  • Mirza S; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Namasivayam V; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Schiedel AC; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Sylvester K; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Thimm D; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Vielmuth C; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Phuong Vu L; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Zyulina M; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Bodem J; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
  • Gütschow M; Institute for Virology and Immunobiology, Julius-Maximilians-University Würzburg, Versbacher Strasse 7, 97078, Würzburg, Germany.
  • Müller CE; Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany), E-mails.
Angew Chem Int Ed Engl ; 60(18): 10423-10429, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-1114156
ABSTRACT
The main protease of SARS-CoV-2 (Mpro ), the causative agent of COVID-19, constitutes a significant drug target. A new fluorogenic substrate was kinetically compared to an internally quenched fluorescent peptide and shown to be ideally suitable for high throughput screening with recombinantly expressed Mpro . Two classes of protease inhibitors, azanitriles and pyridyl esters, were identified, optimized and subjected to in-depth biochemical characterization. Tailored peptides equipped with the unique azanitrile warhead exhibited concomitant inhibition of Mpro and cathepsin L, a protease relevant for viral cell entry. Pyridyl indole esters were analyzed by a positional scanning. Our focused approach towards Mpro inhibitors proved to be superior to virtual screening. With two irreversible inhibitors, azanitrile 8 (kinac /Ki =37 500 m-1 s-1 , Ki =24.0 nm) and pyridyl ester 17 (kinac /Ki =29 100 m-1 s-1 , Ki =10.0 nm), promising drug candidates for further development have been discovered.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 / COVID-19 Drug Treatment / Nitriles Limits: Humans Language: English Journal: Angew Chem Int Ed Engl Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 / COVID-19 Drug Treatment / Nitriles Limits: Humans Language: English Journal: Angew Chem Int Ed Engl Year: 2021 Document Type: Article