A novel class of chikungunya virus small molecule inhibitors that targets the viral capping machinery.

A novel class of chikungunya virus small molecule inhibitors that targets the viral capping machinery. Antimicrob Agents Chemother. 2020 Apr 27;: Authors: Abdelnabi R, Kovacikova K, Moesslacher J, Donckers K, Battisti V, Leyssen P, Langer T, Puerstinger G, Quérat G, Li C, Decroly E, Tas A, Marchand A, Chaltin P, Coutard B, van Hemert M, Neyts J, Delang L Abstract Despite the worldwide re-emergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. We here aim to identify the target of a novel class of CHIKV inhibitors i.e. CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 50% effective concentrations in the low micromolar range. A CHVB-resistant variant (CHVBres) was selected that carried two mutations in the gene encoding nsP1 (responsible for viral RNA capping), one mutation in nsP2 and one mutation in nsP3. Reverse genetics studies demonstrated that both nsP1 mutations were necessary and sufficient to achieve ∼18-fold resistance, suggesting that CHVB targets viral mRNA capping. Interestingly, CHVBres was cross-resistant to the previously described CHIKV capping inhibitors from the MADTP series, suggesting they share a similar mechanism of action. In enzymatic assays, CHVB inhibited the methyltransferase and guanylyltransferase activities of alphavirus nsP1 proteins. To conclude, we identified a...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Tags: Antimicrob Agents Chemother Source Type: research