Novel Class of Chikungunya Virus Small Molecule Inhibitors That Targets the Viral Capping Machinery.
Antimicrob Agents Chemother
; 64(7)2020 06 23.
Article
en En
| MEDLINE
| ID: mdl-32340991
ABSTRACT
Despite the worldwide reemergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. Here, we aimed to identify the target of a novel class of CHIKV inhibitors, i.e., the 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 â¼18-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 class of CHIKV inhibitors that targets the viral capping machinery. The potent anti-CHIKV activity makes this chemical scaffold a potential candidate for CHIKV drug development.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Virus Chikungunya
/
Fiebre Chikungunya
Límite:
Animals
Idioma:
En
Revista:
Antimicrob Agents Chemother
Año:
2020
Tipo del documento:
Article
País de afiliación:
Bélgica