Discovery of a Novel Trifluoromethyl Diazirine Inhibitor of SARS-CoV-2 M<sup>pro</sup>
Andrea Citarella,
Davide Moi,
Martina Pedrini,
Helena Pérez-Peña,
Stefano Pieraccini,
Claudio Stagno,
Nicola Micale,
Tanja Schirmeister,
Giulia Sibille,
Giorgio Gribaudo,
Alessandra Silvani,
Daniele Passarella,
Clelia Giannini
Affiliations
Andrea Citarella
Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy
Davide Moi
Dipartimento di Scienze Chimiche e Geologiche, University of Cagliari, Cittadella Universitaria—S.S. 554 bivio per Sestu, 09042 Monserrato, Italy
Martina Pedrini
Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy
Helena Pérez-Peña
Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy
Stefano Pieraccini
Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy
Claudio Stagno
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy
Nicola Micale
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy
Tanja Schirmeister
Department of Medicinal Chemistry, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany
Giulia Sibille
Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Torino, Italy
Giorgio Gribaudo
Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123 Torino, Italy
Alessandra Silvani
Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy
Daniele Passarella
Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy
Clelia Giannini
Department of Chemistry, University of Milan, Via Golgi 19, 20133 Milano, Italy
SARS-CoV-2 Mpro is a chymotrypsin-like cysteine protease playing a relevant role during the replication and infectivity of SARS-CoV-2, the coronavirus responsible for COVID-19. The binding site of Mpro is characterized by the presence of a catalytic Cys145 which carries out the hydrolytic activity of the enzyme. As a consequence, several Mpro inhibitors have been proposed to date in order to fight the COVID-19 pandemic. In our work, we designed, synthesized and biologically evaluated MPD112, a novel inhibitor of SARS-CoV-2 Mpro bearing a trifluoromethyl diazirine moiety. MPD112 displayed in vitro inhibition activity against SARS-CoV-2 Mpro at a low micromolar level (IC50 = 4.1 μM) in a FRET-based assay. Moreover, an inhibition assay against PLpro revealed lack of inhibition, assuring the selectivity of the compound for the Mpro. Furthermore, the target compound MPD112 was docked within the binding site of the enzyme to predict the established intermolecular interactions in silico. MPD112 was subsequently tested on the HCT-8 cell line to evaluate its effect on human cells’ viability, displaying good tolerability, demonstrating the promising biological compatibility and activity of a trifluoromethyl diazirine moiety in the design and development of SARS-CoV-2 Mpro binders.
