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The protein disulfide isomerase inhibitor 3-methyltoxoflavin inhibits Chikungunya virus. | LitMetric

The protein disulfide isomerase inhibitor 3-methyltoxoflavin inhibits Chikungunya virus.

Bioorg Med Chem

Collaborations Pharmaceuticals, Inc., 840, Main Campus Drive, Lab 3510, Raleigh, NC 27606, USA.

Published: April 2023

AI Article Synopsis

Article Abstract

Chikungunya virus (CHIKV) is the etiological agent of chikungunya fever, a (re)emerging arbovirus infection, that causes severe and often persistent arthritis, as well as representing a serious health concern worldwide for which no antivirals are currently available. Despite efforts over the last decade to identify and optimize new inhibitors or to reposition existing drugs, no compound has progressed to clinical trials for CHIKV and current prophylaxis is based on vector control, which has shown limited success in containing the virus. Our efforts to rectify this situation were initiated by screening 36 compounds using a replicon system and ultimately identified the natural product derivative 3-methyltoxoflavin with activity against CHIKV using a cell-based assay (EC 200 nM, SI = 17 in Huh-7 cells). We have additionally screened 3-methyltoxoflavin against a panel of 17 viruses and showed that it only additionally demonstrated inhibition of the yellow fever virus (EC 370 nM, SI = 3.2 in Huh-7 cells). We have also showed that 3-methyltoxoflavin has excellent in vitro human and mouse microsomal metabolic stability, good solubility and high Caco-2 permeability and it is not likely to be a P-glycoprotein substrate. In summary, we demonstrate that 3-methyltoxoflavin has activity against CHIKV, good in vitro absorption, distribution, metabolism and excretion (ADME) properties as well as good calculated physicochemical properties and may represent a valuable starting point for future optimization to develop inhibitors for this and other related viruses.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150329PMC
http://dx.doi.org/10.1016/j.bmc.2023.117239DOI Listing

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