Targeting the Main Protease of SARS-CoV-2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors
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Open Access
- 25 April 2021
- journal article
- research article
- Published by Wiley in Angewandte Chemie-International Edition
- Vol. 60 (18), 10423-10429
- https://doi.org/10.1002/anie.202016961
Abstract
The main protease of SARS-CoV-2 (M-pro), 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 M-pro. 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 M-pro and cathepsin L, a protease relevant for viral cell entry. Pyridyl indole esters were analyzed by a positional scanning. Our focused approach towards M-pro inhibitors proved to be superior to virtual screening. With two irreversible inhibitors, azanitrile 8 (k(inac)/K-i=37 500 m(-1) s(-1), K-i=24.0 nm) and pyridyl ester 17 (k(inac)/K-i=29 100 m(-1) s(-1), K-i=10.0 nm), promising drug candidates for further development have been discovered.Funding Information
- Bundesministerium für Bildung und Forschung (BIGS DrugS - 16GW0025)
This publication has 52 references indexed in Scilit:
- Design, Synthesis and Biological Evaluation of Potent Azadipeptide Nitrile Inhibitors and Activity‐Based Probes as Promising Anti‐Trypanosoma brucei AgentsChemistry – A European Journal, 2012
- Structural Optimization of Azadipeptide Nitriles Strongly Increases Association Rates and Allows the Development of Selective Cathepsin InhibitorsJournal of Medicinal Chemistry, 2010
- “Click” synthesis of small molecule–peptide conjugates for organelle-specific delivery and inhibition of lysosomal cysteine proteasesChemical Communications, 2010
- Structure–activity relationships of heteroaromatic esters as human rhinovirus 3C protease inhibitorsBioorganic & Medicinal Chemistry Letters, 2009
- Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitorsBioorganic & Medicinal Chemistry Letters, 2008
- Azadipeptide Nitriles: Highly Potent and Proteolytically Stable Inhibitors of Papain‐Like Cysteine ProteasesAngewandte Chemie-International Edition, 2008
- Azadipeptidnitrile – hochpotente und proteolysestabile Inhibitoren Papain-ähnlicher CysteinproteasenAngewandte Chemie, 2008
- Heteroaromatic ester inhibitors of hepatitis A virus 3C proteinase: Evaluation of mode of actionBioorganic & Medicinal Chemistry, 2008
- Determination of Hammett Equation Rho Constant for the Hydrolysis of p-Nitrophenyl Benzoate EstersJournal of Chemical Education, 2008
- Design, Synthesis, and Evaluation of Inhibitors for Severe Acute Respiratory Syndrome 3C-Like Protease Based on Phthalhydrazide Ketones or Heteroaromatic EstersJournal of Medicinal Chemistry, 2007