Assessment of flavaglines as potential chikungunya virus entry inhibitors

Abstract

Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus that recently caused large epidemics in islands in, and countries around, the Indian Ocean. There is currently no specific drug for therapeutic treatment or for use as a prophylactic agent against infection and no commercially available vaccine. Prohibitin has been identified as a receptor protein used by chikungunya virus to enter mammalian cells. Recently, synthetic sulfonyl amidines and flavaglines (FLs), a class of naturally occurring plant compounds with potent anti-cancer and cytoprotective and neuroprotective activities, have been shown to interact directly with prohibitin. This study therefore sought to determine whether three prohibitin ligands (sulfonyl amidine 1 m and the flavaglines FL3 and FL23) were able to inhibit CHIKV infection of mammalian Hek293T/17 cells. All three compounds inhibited infection and reduced virus production when cells were treated before infection but not when added after infection. Pretreatment of cells for only 15 minutes prior to infection followed by washing out of the compound resulted in significant inhibition of entry and virus production. These results suggest that further investigation of prohibitin ligands as potential Chikungunya virus entry inhibitors is warranted.

The Interplay of Viral and Host Factors in Chikungunya Virus Infection: Targets for Antiviral Strategies

“…Wintachai and colleagues also suggested that the possibility of additional co factors that assist the CHIKV entry as poor infection was observed in U937 monocytic cells that also express PHB [124]. In a follow up study, Wintachai and colleagues showed that flavaglines (prohibitin ligand) was able to inhibit CHIKV entry by preventing the CHIKV and prohibitin from colocalising in HEK293T/17 cells [125,126]. These studies suggest that PHB may be the putative receptor for CHIKV.…”

Antivirals Against Chikungunya Virus: Is the Solution in Nature?

“…As CHIKV uses prohibitin as a receptor to entry into mammalian cells [13], Wintachai and colleagues investigated the anti-CHIKV activity of the plant-derived compounds sulfonyl amidines 1M and the flavaglines FL3 and FL23 [41], previously reported to interact with this receptor. These compounds demonstrated antiviral activity against the CHIKV strain E1:226V East-Central-South-Africa (ECSA) genotype of a Thai isolate.…”

Towards antivirals against chikungunya virus

“…Prohibitin-1 was previously identified as a receptor for CHIKV entry into mammalian cells (Wintachai et al, 2012). The synthetic flavaglines sulfonyl amidine 1 m, FL3 and FL23 exert a moderate antiviral effect on CHIKV replication in HEK293T/17 cells (Wintachai et al, 2015). Two compounds (1 m and FL23) were suggested to inhibit an entry step, whereas FL3 could act at a post-entry stage.…”

“…Two compounds (1 m and FL23) were suggested to inhibit an entry step, whereas FL3 could act at a post-entry stage. The co-localization of prohibitin-1 and the CHIKV E2 glycoprotein was markedly reduced in the presence of flavaglines, which may suggest an effect on receptor binding of the virus (Wintachai et al, 2015) (Table 1).…”