Inhibition of the RNA-Dependent RNA-Polymerase from SARS-CoV-2 by 6-Chloropurine Isoxazoline-Carbocyclic Monophosphate Nucleotides

Marco Leusciatti; Beatrice Macchi; Francesca Marino-Merlo; Antonio Mastino; Giulia Morra; Paolo Quadrelli

doi:10.1021/acsomega.3c04918

Inhibition of the RNA-Dependent RNA-Polymerase from SARS-CoV-2 by 6-Chloropurine Isoxazoline-Carbocyclic Monophosphate Nucleotides

ACS Omega. 2023 Sep 20;8(39):36311-36320. doi: 10.1021/acsomega.3c04918. eCollection 2023 Oct 3.

Authors

Marco Leusciatti¹, Beatrice Macchi², Francesca Marino-Merlo³, Antonio Mastino⁴, Giulia Morra⁵, Paolo Quadrelli¹

Affiliations

¹ Department of Chemistry, University of Pavia, Viale Taramelli 12, 27100 Pavia,Italy.
² Department of Chemical Science and Technology, University of Rome Tor Vergata, Via della ricerca scientifica 1, 00133 Roma, Italy.
³ Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy.
⁴ The Institute of Translational Pharmacology, CNR, Via Fosso del Cavaliere 100, 00133 Roma, Italy.
⁵ Biocomputing Lab, SCITEC-Istituto di Scienze e Tecnologie Chimiche CNR, Via Mario Bianco 9, 20131 Milano, Italy.

Abstract

Isoxazoline-carbocyclic monophosphate nucleotides were designed and synthesized through the chemistry of nitrosocarbonyl intermediates and stable anthracenenitrile oxide. Docking and molecular dynamics studies were first conducted for determining the best candidate for polymerase SARS-CoV-2 inhibition. The setup phosphorylation protocol afforded the nucleotides available for the biological tests. Preliminary inhibition and cytotoxicity assays were then performed, and the results showed a moderate activity of the nucleotides accompanied by cytotoxicity.