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Discovery of novel SARS-CoV-2 inhibitors targeting the main protease Mpro by virtual screenings and hit optimization.
Mercorelli, Beatrice; Desantis, Jenny; Celegato, Marta; Bazzacco, Alessandro; Siragusa, Lydia; Benedetti, Paolo; Eleuteri, Michela; Croci, Federico; Cruciani, Gabriele; Goracci, Laura; Loregian, Arianna.
  • Mercorelli B; Department of Molecular Medicine, University of Padua, Padua, Italy.
  • Desantis J; Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy.
  • Celegato M; Department of Molecular Medicine, University of Padua, Padua, Italy.
  • Bazzacco A; Department of Molecular Medicine, University of Padua, Padua, Italy.
  • Siragusa L; Molecular Horizon Srl, Bettona, Italy.
  • Benedetti P; Molecular Discovery Ltd, Centennial Park, Borehamwood, Hertfordshire, United Kingdom.
  • Eleuteri M; Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy.
  • Croci F; Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy.
  • Cruciani G; Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy.
  • Goracci L; Department of Chemistry, Biology, and Biotechnology, University of Perugia, Perugia, Italy. Electronic address: laura.goracci@unipg.it.
  • Loregian A; Department of Molecular Medicine, University of Padua, Padua, Italy. Electronic address: arianna.loregian@unipd.it.
Antiviral Res ; 204: 105350, 2022 08.
Article in English | MEDLINE | ID: covidwho-1944193
ABSTRACT
Two years after its emergence, SARS-CoV-2 still represents a serious and global threat to human health. Antiviral drug development usually takes a long time and, to increase the chances of success, chemical variability of hit compounds represents a valuable source for the discovery of new antivirals. In this work, we applied a platform of variably oriented virtual screening campaigns to seek for novel chemical scaffolds for SARS-CoV-2 main protease (Mpro) inhibitors. The study on the resulting 30 best hits led to the identification of a series of structurally unrelated Mpro inhibitors. Some of them exhibited antiviral activity in the low micromolar range against SARS-CoV-2 and other human coronaviruses (HCoVs) in different cell lines. Time-of-addition experiments demonstrated an antiviral effect during the viral replication cycle at a time frame consistent with the inhibition of SARS-CoV-2 Mpro activity. As a proof-of-concept, to validate the pharmaceutical potential of the selected hits against SARS-CoV-2, we rationally optimized one of the hit compounds and obtained two potent SARS-CoV-2 inhibitors with increased activity against Mpro both in vitro and in a cellular context, as well as against SARS-CoV-2 replication in infected cells. This study significantly contributes to the expansion of the chemical variability of SARS-CoV-2 Mpro inhibitors and provides new scaffolds to be exploited for pan-coronavirus antiviral drug development.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Prognostic study Language: English Journal: Antiviral Res Year: 2022 Document Type: Article Affiliation country: J.antiviral.2022.105350

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Protease Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 Type of study: Prognostic study Language: English Journal: Antiviral Res Year: 2022 Document Type: Article Affiliation country: J.antiviral.2022.105350