Sharma Kiran Bala, Subramani Chandru, Ganesh Khashpatika, Sharma Anshula, Basu Brohmomoy, Balyan Shivani, Sharma Ghanshyam, Ka Shouri, Deb Arundhati, Srivastava Mitul, Chugh Saurabh, Sehrawat Sapna, Bharadwaj Kanchan, Rout Archana, Sahoo Pankaj Kumar, Saurav Suman, Motiani Rajender K, Singh Ramandeep, Jain Deepti, Asthana Shailendra, Wadhwa Renu, Vrati Sudhanshu
Regional Centre for Biotechnology, Faridabad, India.
Translational Health Science and Technology Institute, Faridabad, India.
PLoS Pathog. 2024 Dec 30;20(12):e1012816. doi: 10.1371/journal.ppat.1012816. eCollection 2024 Dec.
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus causing fever, myalgia, and debilitating joint swelling and pain, which in many patients becomes chronic. The frequent epidemics of CHIKV across the world pose a significant public health burden necessitating the development of effective antiviral therapeutics. A cellular imaging-based high-content screening of natural compounds identified withaferin A (WFA), a steroidal lactone isolated from the plant Withania somnifera, as a potent antiviral against CHIKV. In the ERMS cells, WFA inhibited CHIKV replication early during the life cycle by binding the CHIKV non-structural protein nsP2 and inhibiting its protease activity. This inhibited the viral polyprotein processing and the minus-sense viral RNA synthesis. WFA mounted the nsP2 protease inhibitory activity through its oxidising property as the reducing agents N-acetylcysteine and Glutathione-monoethyl ester effectively reversed the WFA-mediated protease inhibition in vitro and abolished the WFA-mediated antiviral activity in cultured cells. WFA inhibited CHIKV replication in the C57BL/6 mouse model of chikungunya disease, resulting in significantly lower viremia. Importantly, CHIKV-infected mice showed significant joint swelling which was not seen in WFA-treated mice. These data demonstrate the potential of WFA as a novel CHIKV antiviral.
基孔肯雅病毒（CHIKV）是一种由蚊子传播的甲病毒，可引起发热、肌痛以及使人衰弱的关节肿胀和疼痛，许多患者的症状会转为慢性。CHIKV在全球频繁流行，造成了重大的公共卫生负担，因此有必要开发有效的抗病毒疗法。一项基于细胞成像的天然化合物高内涵筛选发现，从植物印度人参中分离出的甾体内酯印楝素A（WFA）是一种有效的抗CHIKV病毒药物。在ERMS细胞中，WFA在生命周期早期通过结合CHIKV非结构蛋白nsP2并抑制其蛋白酶活性来抑制CHIKV复制。这抑制了病毒多聚蛋白的加工以及负链病毒RNA的合成。WFA通过其氧化特性发挥nsP2蛋白酶抑制活性，因为还原剂N-乙酰半胱氨酸和谷胱甘肽单乙酯在体外有效逆转了WFA介导的蛋白酶抑制作用，并消除了其在培养细胞中的抗病毒活性。WFA在基孔肯雅病的C57BL/6小鼠模型中抑制了CHIKV复制，导致病毒血症显著降低。重要的是，感染CHIKV的小鼠出现了明显的关节肿胀，而在WFA治疗的小鼠中未观察到这种情况。这些数据证明了WFA作为一种新型抗CHIKV病毒药物的潜力。
