Targeting the Main Protease of SARS‐CoV‐2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors
| Autor: | Salahuddin Mirza, Carina Lemke, Robin Gedschold, Dominik Thimm, Miriam Diett, Nina Geiger, Christa E. Müller, Julian Breidenbach, Michael Gütschow, Jochen Bodem, Christin Vielmuth, Anke C. Schiedel, Katharina Sylvester, Vittoria Lopez, Lan Phuong Vu, Vigneshwaran Namasivayam, Thanigaimalai Pillaiyar, Laura Schäkel, Ghazl Al Hamwi, Maria Zyulina |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Antagonists & inhibitors
Peptidomimetic Pyridines High-throughput screening medicine.medical_treatment Peptide Antiviral Agents Catalysis SARS-CoV-2 main protease fluorogenic substrates Drug Discovery Nitriles medicine Humans Protease Inhibitors SARS‐CoV‐2 Protease Inhibitors Research Articles Coronavirus 3C Proteases chemistry.chemical_classification Virtual screening Protease Drug discovery SARS-CoV-2 COVID-19 General Chemistry Virus Internalization Small molecule High-Throughput Screening Assays COVID-19 Drug Treatment Molecular Docking Simulation HEK293 Cells Biochemistry chemistry Drug Design azapeptide nitriles pyridinyl 1H-indole-carboxylates Research Article high throughput screening |
| Zdroj: | Angewandte Chemie (International Ed. in English) |
| ISSN: | 1521-3773 1433-7851 |
| Popis: | 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. The main protease (Mpro) of SARS‐CoV‐2 has been recognized as a significant drug target to treat COVID‐19. The design of a new fluorogenic substrate, the recombinant expression of Mpro and the development of an HTS assay were combined with a structure‐based rational approach leading to the discovery of tailored azanitriles and indole pyridyl esters as novel, outstandingly potent Mpro inhibitors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text