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- Title
Withaferin A inhibits Chikungunya virus nsP2 protease and shows antiviral activity in the cell culture and mouse model of virus infection.
- Authors
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
- Abstract
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. Author summary: Chikungunya virus (CHIKV) spreads through the bites of the infected mosquitoes, and causes chikungunya fever involving severe joint and muscle pain. Epidemics of chikungunya fever are frequent, and the virus has become endemic in several regions. The virus has been reported from over 100 countries in Asia, Africa, South and Central America, and Europe, affecting almost half a million individuals annually. A CHIKV vaccine has recently been approved; however, no CHIKV-specific antiviral therapy is available. Considering the vast geographic spread of the virus and the large number of infections, developing novel CHIKV antivirals is an important public health priority. We screened small molecules from medicinal plants for anti-CHIKV activity and identified withaferin A (WFA) from the plant Withania sominifera as inhibiting virus replication in the cultured cells. CHIKV-infected mice treated with WFA showed reduced virus replication and no CHIKV infection symptoms. Our studies show that WFA binds the CHIKV protease and inhibits its action, which is necessary for producing the critical viral proteins for its replication. Our work has thus identified WFA as a novel CHIKV antiviral that may be studied further for its human use.
- Subjects
CHIKUNGUNYA; CHIKUNGUNYA virus; JOINT diseases; JOINT pain; VIRUS diseases
- Publication
PLoS Pathogens, 2024, Vol 20, Issue 12, p1
- ISSN
1553-7366
- Publication type
Academic Journal
- DOI
10.1371/journal.ppat.1012816