Journal article

Authors list: Previti, Santo; Ettari, Roberta; Calcaterra, Elsa; Di Maro, Salvatore; Hammerschmidt, Stefan J.; Mueller, Christin; Ziebuhr, John; Schirmeister, Tanja; Cosconati, Sandro; Zappala, Maria

Publication year: 2023

Journal: European Journal of Medicinal Chemistry

Volume number: 247

ISSN: 0223-5234

eISSN: 1768-3254

Open access status: Green

DOI Link: https://doi.org/10.1016/j.ejmech.2022.115021

Publisher: Elsevier

Abstract: 
Despite several major achievements in the development of vaccines and antivirals, the fight against SARS-CoV-2 and the health problems accompanying COVID-19 are still ongoing. SARS-CoV-2 main protease (Mpro), an essential viral cysteine protease, is a crucial target for the development of antiviral agents. A virtual screening analysis of in-house cysteine protease inhibitors against SARS-CoV-2 Mpro allowed us to identify two hits (i.e., 1 and 2) bearing a methyl vinyl ketone warhead. Starting from these compounds, we herein report the development of Michael acceptors targeting SARS-CoV-2 Mpro, which differ from each other for the warhead and for the amino acids at the P2 site. The most promising vinyl methyl ketone-containing analogs showed sub-micromolar activity against the viral protease. SPR38, SPR39, and SPR41 were fully characterized, and additional inhibitory properties towards hCatL, which plays a key role in the virus entry into host cells, were observed. SPR39 and SPR41 exhibited single-digit micromolar EC50 values in a SARS-CoV-2 infection model in cell culture.

Harvard Citation style: Previti, S., Ettari, R., Calcaterra, E., Di Maro, S., Hammerschmidt, S., Mueller, C., et al. (2023) Structure-based lead optimization of peptide-based vinyl methyl ketones as SARS-CoV-2 main protease inhibitors, European Journal of Medicinal Chemistry, 247, Article 115021. https://doi.org/10.1016/j.ejmech.2022.115021

APA Citation style: Previti, S., Ettari, R., Calcaterra, E., Di Maro, S., Hammerschmidt, S., Mueller, C., Ziebuhr, J., Schirmeister, T., Cosconati, S., & Zappala, M. (2023). Structure-based lead optimization of peptide-based vinyl methyl ketones as SARS-CoV-2 main protease inhibitors. European Journal of Medicinal Chemistry. 247, Article 115021. https://doi.org/10.1016/j.ejmech.2022.115021