α‑Ketoamides as Broad-Spectrum Inhibitors\nof Coronavirus and Enterovirus Replication: Structure-Based Design,\nSynthesis, and Activity Assessment

Résumé fourni par la source

The main protease of coronaviruses\nand the 3C protease of enteroviruses\nshare a similar active-site architecture and a unique requirement\nfor glutamine in the P1 position of the substrate. Because of their\nunique specificity and essential role in viral polyprotein processing,\nthese proteases are suitable targets for the development of antiviral\ndrugs. In order to obtain near-equipotent, broad-spectrum antivirals\nagainst alphacoronaviruses, betacoronaviruses, and enteroviruses,\nwe pursued a structure-based design of peptidomimetic α-ketoamides\nas inhibitors of main and 3C proteases. Six crystal structures of\nprotease–inhibitor complexes were determined as part of this\nstudy. Compounds synthesized were tested against the recombinant proteases\nas well as in viral replicons and virus-infected cell cultures; most\nof them were not cell-toxic. Optimization of the P2 substituent of\nthe α-ketoamides proved crucial for achieving near-equipotency\nagainst the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclohexylmethyl),\ndisplay low-micromolar EC50 values against enteroviruses,\nalphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7\ncells, 11r exhibits three-digit picomolar activity against\nthe Middle East Respiratory Syndrome coronavirus.

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