Division of Virology, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road Scheme- XM, Beliaghata, Kolkata 700010, India.
Division of Virology, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road Scheme- XM, Beliaghata, Kolkata 700010, India.
Antiviral Res. 2019 Jan;161:53-62. doi: 10.1016/j.antiviral.2018.11.009. Epub 2018 Nov 19.
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.
轮状病毒（RV）感染引起的急性水样腹泻与社会经济背景较差国家婴儿发病率和死亡率高有关。虽然在发达国家显示出良好的趋势，但在疾病负担高的社会经济贫困地区，目前许可的 RV 疫苗的效果并不理想。目前，除了经典的疫苗接种方案外，没有批准的抗轮状病毒药物。有趣的是，对宿主-轮状病毒相互作用的剖析产生了新型的、不可变的宿主决定因素，这些因素可以通过选择性小分子进行干预。本研究旨在评估最近发现的小分子 RA-839 抗 RV 的潜力，该小分子对细胞氧化应激敏感的核因子红细胞衍生 2 样 2（Nrf2）/抗氧化反应元件（ARE）途径具有强大且高度选择性的激动活性。体外研究表明，RA-839 抑制 RV RNA 和蛋白表达、病毒空斑形成、病毒粒子后代产量和病毒诱导的细胞病变，而与 RV 株、RV 允许的细胞系无关，且无旁观者细胞毒性。RA-839 的抗 RV 效力随后被确定为独立于随机干扰素（IFN）刺激，但依赖于 RA-839 刺激 Nrf2/ARE 信号的能力。有趣的是，RA-839 的抗 rotaviral 作用也被 2-氰基-3,12-二氧代-1,9(11)-二烯-28-酸甲酯（CDDO-Me）和血红素模拟，这两种是 Nrf2/ARE 途径的经典药理学激活剂。总的来说，这项研究强调了 RA-839 是一种在体外抑制 RV 增殖的有效拮抗剂，并可开发为抗 rotaviral 治疗药物。
