Identification of tyrphostin AG879 and A9 inhibiting replication of
Chikungunya virus by screening of a kinase inhibitor library
Abstract
Chikungunya virus (CHIKV) is a globally public health threat. There are
currently no medications available to treat CHIKV infection.
High-throughput screening of 419 kinase inhibitors was performed based
on the cytopathic effect method, and six kinase inhibitors with reduced
cytopathic effects, including tyrphostin AG879 (AG879), tyrphostin 9
(A9), sorafenib, sorafenib tosylate, regorafenib, and TAK-632, were
identified. The anti-CHIKV activities of two receptor tyrosine kinase
inhibitors, AG879 and A9, that have not been previously reported, were
selected for further evaluation. The results indicated that 50%
cytotoxic concentration (CC 50) of AG879 and A9 in Vero
cells were greater that than 30 μM and 6.50 μM, respectively and 50%
effective concentration (EC 50) were 0.84 μM and 0.36
μM, respectively. The time-of-addition and time-of-removal assays
illustrated that both AG879 and A9 function in the middle stage of CHIKV
life cycle. Further, AG879 and A9 do not affect viral attachment;
however, they inhibit viral RNA replication, and exhibit antiviral
activity against CHIKV Eastern/Central/South African and Asian strains,
Ross River virus and Sindbis virus in vitro.