RA-839, a selective agonist of Nrf2/ARE pathway, exerts potent anti-rotaviral efficacy in vitro

Abstract

Acute watery diarrhea due to Rotavirus (RV) infection is associated with high infantile morbidity and mortality in countries with compromised socio-economic backgrounds. Although showing promising trends in developed countries, the efficacy of currently licensed RV vaccines is sub-optimal in socio-economically poor settings with high disease burden. Currently, there are no approved anti-rotaviral drugs adjunct to classical vaccination program. Interestingly, dissecting host-rotavirus interaction has yielded novel, non-mutable host determinants which can be subjected to interventions by selective small molecules. The present study was undertaken to evaluate the anti-RV potential of RA-839, a recently discovered small molecule with potent and highly selective agonistic activity towards cellular redox stress-sensitive Nuclear factor erytheroid-derived-2-like 2 (Nrf2)/Antioxidant Response Element (ARE) pathway. In vitro studies revealed that RA-839 inhibits RV RNA and protein expression, viroplasm formation, yield of virion progeny and virus-induced cytopathy independent of RV strains, RV-permissive cell lines and without bystander cytotoxicity. Anti-RV potency of RA-839 was subsequently identified to be independent of stochastic Interferon (IFN) stimulation but to be dependent on RA-839's ability to stimulate Nrf2/ARE signaling. Interestingly, anti-rotaviral effects of RA-839 were also mimicked by 2-Cyano-3, 12-dioxo-oleana-1, 9(11)-dien-28-oic acid methyl ester (CDDO-Me) and Hemin, two classical pharmacological activators of Nrf2/ARE pathway. Overall, this study highlights that RA-839 is a potent antagonist of RV propagation in vitro and can be developed as anti-rotaviral therapeutics.