Roux H., Touret Franck, Coluccia A., Khoumeri O., Di Giorgio C., Majdi C., Sciò P., Silvestri R., Vanelle P., Roche M. (2024). New potent EV-A71 antivirals targeting capsid. European Journal of Medicinal Chemistry, 276, 116658 [18 p.]. ISSN 0223-5234.
Auteurs
Roux H., Touret Franck, Coluccia A., Khoumeri O., Di Giorgio C., Majdi C., Sciò P., Silvestri R., Vanelle P., Roche M.
Source
European Journal of Medicinal Chemistry, 2024,
276, 116658 [18 p.] ISSN 0223-5234
The enterovirus is a genus of single-stranded, highly diverse positive-sense RNA viruses, including Human Enterovirus A-D and Human Rhinovirus A-C species. They are responsible for numerous diseases and some infections can progress to life-threatening complications, particularly in children or immunocompromised patients. To date, there is no treatment against enteroviruses on the market, except for polioviruses (vaccine) and EV-A71 (vaccine in China). Following a decrease in enterovirus infections during and shortly after the (SARS-Cov2) lockdown, enterovirus outbreaks were once again detected, notably in young children. This reemergence highlights on the need to develop broad-spectrum treatment against enteroviruses. Over the last year, our research team has identified a new class of small-molecule inhibitors showing anti-EV activity. Targeting the well-known hydrophobic pocket in the viral capsid, these compounds show micromolar activity against EV-A71 and a high selectivity index (SI) (5h: EC50, MRC-5 = 0.57 ?M, CC50, MRC-5 >20 ?M, SI > 35; EC50, RD = 4.38 ?M, CC50, RD > 40 ?M, SI > 9; 6c: EC50, MRC-5 = 0.29 ?M, CC50, MRC-5 >20 ?M, SI > 69; EC50, RD = 1.66 ?M, CC50, RD > 40 ?M, SI > 24; Reference: Vapendavir EC50, MRC-5 = 0.36 ?M, CC50, MRC-5 > 20 ?M, EC50, RD = 0.53 ?M, CC50, RD > 40 ?M, SI > 63). The binding mode of these compounds in complex with enterovirus capsids was analyzed and showed a series of conserved interactions. Consequently, 6c and its derivatives are promising candidates for the treatment of enterovirus infections.
