Discovery of a Novel Inhibitor for Chikungunya Virus

Chikungunya virus (CHIKV) is the etiological agent of chikungunya fever, a (re)emerging arbovirus infection, that causes severe and often persistent arthritis, representing a serious health problem worldwide for which no antivirals are currently available. Despite the efforts over the last decade to identify and optimize new inhibitors or to reposition existing drugs, no compound has progressed to clinical trials and prophylaxis is based on vector control, which has shown limited success in containing the virus. Herein, we screened 36 compounds using a replicon system and ultimately identified 3-methyltoxoflavin with activity against CHIKV using cell assays (EC50 200 nM). We have additionally screened 3-methyltoxoflavin against a panel of viruses and showed that it also inhibits yellow fever virus (IC50 370 nM, SI=3.2 in Huh-7 cells). 3-methyltoxoflavin is a known protein disulfide isomerase (PDI) inhibitor, and inhibitor of alphaviruses which likely depends on this host protein to aid in facilitating disulfide bond formation and isomerization, since alphaviruses require conserved cysteine residues for proper folding and assembly of the E1 and E2 envelope glycoproteins. In summary we demonstrate that 3-methyltoxoflavin has activity against CHIKV and may represent a starting point for optimization to develop inhibitors to this and other viruses.