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Article

Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses

1
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, V.le F. Stagno d’Alcontres 31, 98166 Messina, Italy
2
Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
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Department of Drug Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy
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Department of Life Sciences and Systems Biology, University of Torino, Via Accademia Albertina 13, 10123 Torino, Italy
5
Department of Chemistry, University of Torino, Via P. Giuria 7, 10125 Torino, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: Fabio Altieri
Int. J. Mol. Sci. 2021, 22(3), 1398; https://doi.org/10.3390/ijms22031398
Received: 22 December 2020 / Accepted: 26 January 2021 / Published: 30 January 2021
(This article belongs to the Section Molecular Informatics)
The synthesis of α-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl α,α-difluoromethyl ketone (DFMK) 8 as a potential antiviral agent with activity against human coronaviruses. The ability of the newly synthesized compound to inhibit viral replication was evaluated by a viral cytopathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coronaviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC50 = 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC50 = 170 ± 3.79 µM, 307 ± 11.63 µM, and 174 ± 7.6 µM for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8 efficaciously binds to the intended target hCoV-229E main protease (Mpro). Moreover, due to the high similarity between hCoV-229E Mpro and SARS-CoV-2 Mpro, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E Mpro and promising in terms of energy of binding and docking pose. View Full-Text
Keywords: coronavirus; cysteine proteases; hCoV-229E; SARS-CoV-2 Mpro; difluoromethyl ketone coronavirus; cysteine proteases; hCoV-229E; SARS-CoV-2 Mpro; difluoromethyl ketone
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MDPI and ACS Style

Citarella, A.; Gentile, D.; Rescifina, A.; Piperno, A.; Mognetti, B.; Gribaudo, G.; Sciortino, M.T.; Holzer, W.; Pace, V.; Micale, N. Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses. Int. J. Mol. Sci. 2021, 22, 1398. https://doi.org/10.3390/ijms22031398

AMA Style

Citarella A, Gentile D, Rescifina A, Piperno A, Mognetti B, Gribaudo G, Sciortino MT, Holzer W, Pace V, Micale N. Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses. International Journal of Molecular Sciences. 2021; 22(3):1398. https://doi.org/10.3390/ijms22031398

Chicago/Turabian Style

Citarella, Andrea; Gentile, Davide; Rescifina, Antonio; Piperno, Anna; Mognetti, Barbara; Gribaudo, Giorgio; Sciortino, Maria T.; Holzer, Wolfgang; Pace, Vittorio; Micale, Nicola. 2021. "Pseudo-Dipeptide Bearing α,α-Difluoromethyl Ketone Moiety as Electrophilic Warhead with Activity against Coronaviruses" Int. J. Mol. Sci. 22, no. 3: 1398. https://doi.org/10.3390/ijms22031398

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