| Autor: |
De Castro S; Instituto de Química Médica (IQM, CSIC), E-28006 Madrid, Spain., Stevaert A; Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium., Maldonado M; Instituto de Química Médica (IQM, CSIC), E-28006 Madrid, Spain., Delpal A; AFMB, UMR 7257, CNRS, Aix Marseille Université, 13288 Marseille, France., Vandeput J; Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium., Van Loy B; Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium., Eydoux C; AFMB, UMR 7257, CNRS, Aix Marseille Université, 13288 Marseille, France., Guillemot JC; AFMB, UMR 7257, CNRS, Aix Marseille Université, 13288 Marseille, France., Decroly E; AFMB, UMR 7257, CNRS, Aix Marseille Université, 13288 Marseille, France., Gago F; Unidad Asociada al IQM-CSIC, Área de Farmacología, Departamento de Ciencias Biomédicas, Universidad de Alcalá, E-28805 Alcalá de Henares, Spain., Canard B; AFMB, UMR 7257, CNRS, Aix Marseille Université, 13288 Marseille, France., Camarasa MJ; Instituto de Química Médica (IQM, CSIC), E-28006 Madrid, Spain., Velázquez S; Instituto de Química Médica (IQM, CSIC), E-28006 Madrid, Spain., Naesens L; Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium. |
| Abstrakt: |
There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure-activity relationship of these structurally unique inhibitors. Despite the presence of five points of diversity, the synthesis of an extensive series of analogues was readily achieved by Ugi four-component reaction from commercially available reagents. After evaluating 63 analogues against human coronavirus 229E, four of the best molecules were selected and shown to have micromolar activity against SARS-CoV-2. Since the action point was situated post virus entry and lying at the stage of viral polyprotein processing and the start of RNA synthesis, enzymatic assays were performed with CoV proteins involved in these processes. While no inhibition was observed for SARS-CoV-2 nsp12-nsp7-nsp8 polymerase, nsp14 N7-methyltransferase and nsp16/nsp10 2'-O-methyltransferase, nor the nsp3 papain-like protease, the compounds clearly inhibited the nsp5 main protease (M pro ). Although the inhibitory activity was quite modest, the plausibility of binding to the catalytic site of M pro was established by in silico studies. Therefore, the 1,4,4-trisubstituted piperidines appear to represent a novel class of non-covalent CoV M pro inhibitors that warrants further optimization and development. |
