Alpha ketoamides as broad spectrum inhibitors of coronavirus and enterovirus replication : Structure Based design and synthesis
Trupti Musne, Sangram U. Deshmukh, Vidyasagar Gali, Shyamlila B. Bavage, Nandkishor B. Bavage
Picornaviruses are small non-enveloped RNA viruses with genomic RNA of 7500 – 8000 nucleotides, whereas coronaviruses (CoV)are RNA viruses with larger genome of 27 – 32 kb. Both types of viruses translate their genetic information into polyprotein precursors that are processed by virally encoded 3C proteases (3Cpro) and 3C-like proteases (3CLpro),respectively, to generate functional viral proteins. The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs.In this review we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u and11r display low-micromolar EC50 values against enteroviruses, alphacoronaviruses,and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respirator Syndrome coronavirus.