Viral methyltransferase inhibitors: berbamine, venetoclax, and ponatinib as efficacious antivirals against Chikungunya virus

Chikungunya virus (CHIKV), transmitted by mosquitoes, poses a significant global health threat. Presently, no effective treatment options are available to reduce the disease burden. The lack of approved therapeutics against CHIKV and the complex spectrum of chronic musculoskeletal and neurological manifestations raise significant concerns, and repurposing drugs could offer swift avenues in the development of effective treatment strategies. RNA capping is a crucial step meditated by non-structural protein 1 (nsP1) in CHIKV replication. In this study, FDA-approved antivirals targeting CHIKV nsP1 methyltransferase (MTase) have been identified by structure-based virtual screening. Berbamine Hydrochloride (BH), ABT199/Venetoclax (ABT), and Ponatinib (PT) were the top hits, which exhibited robust binding energies. Tryptophan fluorescence spectroscopy-based assay confirmed binding of BH-, ABT-, and PT to purified nsP1 with KD values [~]5.45 M, [~]161.3 M, and [~]3.83M, respectively. A dose-dependent decrease in CHIKV nsP1 MTase activity was observed in a capillary electrophoresis-based assay. Treatment with BH, ABT, and PT lead to a dose-dependent reduction in the virus titer with IC50 1.25 M, respectively. These results underscore the efficacy and promise of repurposing drugs as rapid and effective antiviral therapeutics against CHIKV. HighlightsO_LIBerbamine Hydrochloride (BH), ABT199/Venetoclax (ABT), and Ponatinib (PT) identified as inhibitors of Chikungunya virus (CHIKV) nsP1 C_LIO_LIMolecules BH, ABT and PT make moelcular interactions with nsP1: KD values [~]5.45, [~]161.3, and [~]3.83 in M, respectively and effectively inhibit methyltransferase activity. C_LIO_LIBH, ABT, and PT exhibited potent antiviral activity against CHIKV in cell-based assays, with IC50 1.25 M respectively demonstrating broad spectrum antiviral efficacy. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/594723v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1af985dorg.highwire.dtl.DTLVardef@13c14fforg.highwire.dtl.DTLVardef@1868785org.highwire.dtl.DTLVardef@12b690a_HPS_FORMAT_FIGEXP M_FIG C_FIG