Targeting host inducible-heat shock protein 70 with PES-Cl is a promising antiviral strategy against SARS-CoV-2 infection and pathogenesis

One of the fundamental mechanisms developed by the host to contain the highly infectious and rapidly proliferating SARS-coronavirus is elevation of body temperature, a natural fallout of which is heat shock proteins over-expression. Here, for the first time, we demonstrate that the SARS-CoV-2 exploi...

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Published in:International journal of biological macromolecules 2024-11, Vol.279 (Pt 1), p.135069, Article 135069
Main Authors: Joshi, Prerna, Garg, Swati, Mani, Shailendra, Shoaib, Rumaisha, Jakhar, Kamini, Almuqdadi, Haider Thaer Abdulhameed, Sonar, Sudipta, Marothia, Manisha, Behl, Ankita, Biswas, Shreeja, Singhal, Jhalak, Kahlon, Amandeep Kaur, Shevtsov, Maxim, Abid, Mohammad, Garg, Pramod, Ranganathan, Anand, Singh, Shailja
Format: Article
Language:English
Subjects:
Angiotensin converting enzyme-2 (ACE2)
Autophagy
Hsp70
PES-Cl
Receptor binding domain (RBD)
SARS-CoV-2
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Summary:One of the fundamental mechanisms developed by the host to contain the highly infectious and rapidly proliferating SARS-coronavirus is elevation of body temperature, a natural fallout of which is heat shock proteins over-expression. Here, for the first time, we demonstrate that the SARS-CoV-2 exploits the host Heat shock protein 70 (Hsp70) chaperone for its entry and propagation, and blocking it can combat the infection. SARS-CoV-2 infection as well as febrile temperature enhanced Hsp70 expression in host Vero E6 cells. Furthermore, heat shock or viral infection elevated the host cell autophagic response which is a prerequisite for viral propagation. In addition, Hsp70 protein demonstrated strong interaction with host Angiotensin-converting enzyme 2 (ACE2) as well as the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, indicating that interaction of Hsp70 with ACE2 and Spike protein may serve to protect them during febrile conditions. Suppressive and prophylactic treatment of Vero E6 cells with Hsp70 inhibitor PES, 2-(3-chlorophenyl) ethynesulfonamide (PES-Cl), abrogated viral infection more potently than the currently used drug Remdesivir. In conclusion, our study not only provides a fundamental insight into the role of host Hsp70 in SARS-CoV-2 pathogenesis, it paves the way for development of potent and irresistible anti-viral therapeutics.
ISSN:0141-8130
1879-0003
1879-0003
DOI:10.1016/j.ijbiomac.2024.135069