Abstract
SARS-CoV-2 is the coronavirus causing the catastrophic pandemic which already led to >120 millions of infections and >2.6 millions of deaths. Hydroxychloroquine (HCQ) has been shown to own promising potential in clinically combating SARS-CoV-2 but the underlying mechanisms still remain almost unknown. So far, all action sites are proposed on the host cells, and in particular no specific viral target protein has been experimentally identified. In this study, by use of DIC microscopy and NMR spectroscopy, for the first time we have decoded that HCQ specifically binds to both N-terminal domain (NTD) and C-terminal domain (CTD) of SARS-CoV-2 nucleocapsid (N) protein to inhibit their interactions with nucleic acids (NAs), as well as to disrupt its NA-induced liquid-liquid phase separation (LLPS) essential for the viral life cycle including the package of gRNA and N protein into new virions. These results suggest that HCQ may achieve its anti-SARS-CoV-2 activity by interfering in several key steps of the viral life cycle. The study not only provides a structural basis for the anti-SARS-CoV-2 activity of HCQ, but also indicates that SARS-CoV-2 N protein and its LLPS represent key targets for further optimization and development of anti-SARS-CoV-2 drugs.
Competing Interest Statement
The authors have declared no competing interest.
