期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 244, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114857
关键词
SARS-CoV-2; Molecular modeling; X-ray crystallography; Antiviral; Covalent inhibitors
资金
- FRISBI [ANR-10-INBS-0005-02]
- GRAL [ANR-17-EURE-0003]
Despite the effectiveness of vaccines in mitigating the spread of SARS-CoV-2, therapeutics offer additional benefits in controlling viral transmission. This study developed tripeptide derivatives targeting SARS-CoV-2 Mpro and identified compound 58 as a promising candidate with improved antiviral activity against variants and safety in vitro and in vivo. These findings suggest the potential of compound 58 for intranasal administration.
Although vaccines are greatly mitigating the worldwide pandemic diffusion of SARS-Cov-2, therapeutics should provide many distinct advantages as complementary approach to control the viral spreading. Here, we report the development of new tripeptide derivatives of AT1001 against SARS-CoV-2 Mpro. By molecular modeling, a small compound library was rationally designed and filtered for enzymatic inhibition through FRET assay, leading to the identification of compound 4. X-ray crystallography studies provide insights into its binding mode and confirm the formation of a covalent bond with Mpro C145. In vitro antiviral tests indicate the improvement of biological activity of 4 respect to AT1001. In silico and X-ray crystallography analysis led to 58, showing a promising activity against three SARS-CoV-2 variants and a valuable safety in Vero cells and human embryonic lung fibroblasts. The drug tolerance was also confirmed by in vivo studies, along with pharmacokinetics evalu-ation. In summary, 58 could pave the way to develop a clinical candidate for intranasal administration.
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