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Identification of Inhibitors of SARS-CoV-2 3CL-Pro Enzymatic Activity Using a Small Molecule in Vitro Repurposing Screen.
Kuzikov, Maria; Costanzi, Elisa; Reinshagen, Jeanette; Esposito, Francesca; Vangeel, Laura; Wolf, Markus; Ellinger, Bernhard; Claussen, Carsten; Geisslinger, Gerd; Corona, Angela; Iaconis, Daniela; Talarico, Carmine; Manelfi, Candida; Cannalire, Rolando; Rossetti, Giulia; Gossen, Jonas; Albani, Simone; Musiani, Francesco; Herzog, Katja; Ye, Yang; Giabbai, Barbara; Demitri, Nicola; Jochmans, Dirk; Jonghe, Steven De; Rymenants, Jasper; Summa, Vincenzo; Tramontano, Enzo; Beccari, Andrea R; Leyssen, Pieter; Storici, Paola; Neyts, Johan; Gribbon, Philip; Zaliani, Andrea.
  • Kuzikov M; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Schnackenburgallee 114, 22525 Hamburg, Germany.
  • Costanzi E; Elettra-Sincrotrone Trieste S.C.p.A., SS 14 - km 163, 5 in AREA Science Park, 34149 Basovizza, Trieste, Italy.
  • Reinshagen J; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Schnackenburgallee 114, 22525 Hamburg, Germany.
  • Esposito F; Dipartimento di Scienze della vita e dell'ambiente, Cittadella Universitaria di Monserrato, SS-554 Monserrato, Cagliari, Italy.
  • Vangeel L; Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Herestraat 49, Box 1043, 3000 Leuven, Belgium.
  • Wolf M; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Schnackenburgallee 114, 22525 Hamburg, Germany.
  • Ellinger B; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Schnackenburgallee 114, 22525 Hamburg, Germany.
  • Claussen C; Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Schnackenburgallee 114, 22525 Hamburg, Germany.
  • Geisslinger G; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor Stern Kai 7, 60596 Frankfurt am Main, Germany.
  • Corona A; Institute of Clinical Pharmacology, Goethe-University, Theodor Stern Kai 7, 60590 Frankfurt, Germany.
  • Iaconis D; Dipartimento di Scienze della vita e dell'ambiente, Cittadella Universitaria di Monserrato, SS-554 Monserrato, Cagliari, Italy.
  • Talarico C; Dompé Farmaceutici SpA, via Campo di Pile, 67100 L'Aquila, Italy.
  • Manelfi C; Dompé Farmaceutici SpA, via Campo di Pile, 67100 L'Aquila, Italy.
  • Cannalire R; Dompé Farmaceutici SpA, via Campo di Pile, 67100 L'Aquila, Italy.
  • Rossetti G; Department of Pharmacy, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy.
  • Gossen J; Institute of Neuroscience and Medicine (INM-9)/Institute for Advanced Simulation (IAS-5) and Jülich Supercomputing Centre (JSC) Forschungszentrum Jülich, D-52425 Jülich, Germany.
  • Albani S; Faculty of Medicine, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany.
  • Musiani F; Institute of Neuroscience and Medicine (INM-9)/Institute for Advanced Simulation (IAS-5) and Jülich Supercomputing Centre (JSC) Forschungszentrum Jülich, D-52425 Jülich, Germany.
  • Herzog K; Institute of Neuroscience and Medicine (INM-9)/Institute for Advanced Simulation (IAS-5) and Jülich Supercomputing Centre (JSC) Forschungszentrum Jülich, D-52425 Jülich, Germany.
  • Ye Y; Laboratory of Bioinorganic Chemistry, Department of Pharmacy and Biotechnology, University of Bologna, 40216 Bologna, Italy.
  • Giabbai B; EU-OPENSCREEN ERIC, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
  • Demitri N; University of Chinese Academy of Sciences, Beijing 100049, China.
  • Jochmans D; Elettra-Sincrotrone Trieste S.C.p.A., SS 14 - km 163, 5 in AREA Science Park, 34149 Basovizza, Trieste, Italy.
  • Jonghe S; Elettra-Sincrotrone Trieste S.C.p.A., SS 14 - km 163, 5 in AREA Science Park, 34149 Basovizza, Trieste, Italy.
  • Rymenants J; Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Herestraat 49, Box 1043, 3000 Leuven, Belgium.
  • Summa V; Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Herestraat 49, Box 1043, 3000 Leuven, Belgium.
  • Tramontano E; Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Herestraat 49, Box 1043, 3000 Leuven, Belgium.
  • Beccari AR; Department of Pharmacy, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy.
  • Leyssen P; Dipartimento di Scienze della vita e dell'ambiente, Cittadella Universitaria di Monserrato, SS-554 Monserrato, Cagliari, Italy.
  • Storici P; Dompé Farmaceutici SpA, via Campo di Pile, 67100 L'Aquila, Italy.
  • Neyts J; Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Herestraat 49, Box 1043, 3000 Leuven, Belgium.
  • Gribbon P; Elettra-Sincrotrone Trieste S.C.p.A., SS 14 - km 163, 5 in AREA Science Park, 34149 Basovizza, Trieste, Italy.
  • Zaliani A; Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Herestraat 49, Box 1043, 3000 Leuven, Belgium.
ACS Pharmacol Transl Sci ; 4(3): 1096-1110, 2021 Jun 11.
Article in English | MEDLINE | ID: covidwho-1313542
ABSTRACT
Compound repurposing is an important strategy for the identification of effective treatment options against SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (3CL-Pro), also termed M-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyproteins pp1a and pp1ab at multiple distinct cleavage sites. We here report the results of a repurposing program involving 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and small molecules regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro and have identified 62 additional compounds with IC50 values below 1 µM and profiled their selectivity toward chymotrypsin and 3CL-Pro from the Middle East respiratory syndrome virus. A subset of eight inhibitors showed anticytopathic effect in a Vero-E6 cell line, and the compounds thioguanosine and MG-132 were analyzed for their predicted binding characteristics to SARS-CoV-2 3CL-Pro. The X-ray crystal structure of the complex of myricetin and SARS-Cov-2 3CL-Pro was solved at a resolution of 1.77 Å, showing that myricetin is covalently bound to the catalytic Cys145 and therefore inhibiting its enzymatic activity.

Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Journal: ACS Pharmacol Transl Sci Year: 2021 Document Type: Article Affiliation country: Acsptsci.0c00216

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Journal: ACS Pharmacol Transl Sci Year: 2021 Document Type: Article Affiliation country: Acsptsci.0c00216