Withaferin A inhibits Chikungunya virus nsP2 protease and shows antiviral activity in the cell culture and mouse model of virus infection
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.
Authors
- Pankaj Kumar Sahoo (ORCID: https://orcid.org/0000-0001-6609-5725)
- Brohmomoy Basu (ORCID: https://orcid.org/0000-0001-6280-8732)
- Shailendra Asthana (ORCID: https://orcid.org/0000-0002-4203-9849)
- Saurabh Chugh (ORCID: https://orcid.org/0000-0003-0195-3375)
- Amit Rout (ORCID: https://orcid.org/0000-0002-0911-240X)
- Deepti Jain (ORCID: https://orcid.org/0000-0002-8631-7230)
- Shouri KA
- Chandru Subramani (ORCID: https://orcid.org/0000-0001-5002-3807)
- Kiran Bala Sharma (ORCID: https://orcid.org/0000-0002-2575-4525)
- Mitul Srivastava
- Sudhanshu Vrati (ORCID: https://orcid.org/0000-0002-9984-3897)
- Renu Wadhwa (ORCID: https://orcid.org/0000-0001-8248-5192)
- Kuchimanchi K. Bharadwaj
- Sapna Sehrawat (ORCID: https://orcid.org/0009-0008-5795-4258)
- Ganesh Kondabattula (ORCID: https://orcid.org/0000-0002-2305-1797)
- Arundhati Deb (ORCID: https://orcid.org/0000-0001-6951-5617)
- Ghanshyam Sharma (ORCID: https://orcid.org/0000-0003-0661-7223)
- Rajender K. Motiani (ORCID: https://orcid.org/0000-0002-8971-9008)
- Ramandeep Singh (ORCID: https://orcid.org/0000-0003-2705-3826)
- Anshula Sharma
- Suman Saurav
- Shivani Balyan
Institutions
- Translational Health Science and Technology Institute (IN)
- Regional Centre for Biotechnology (IN)
- National Institute of Advanced Industrial Science and Technology (JP)
Publication Details
- Journal
- PLoS Pathogens
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1371/journal.ppat.1012816
- Citations
- 11
- Primary Topic
- Phytochemicals and Medicinal Plants
- Type
- article
- Field-Weighted Citation Impact
- 7.88
Funders
- Department of Biotechnology, Ministry of Science and Technology, India
- Science and Engineering Research Board