SARS-CoV-2 is the coronavirus causing the ongoing pandemic which already led to >129 millions of infections and >2.8 millions of deaths. Hydroxychloroquine (HCQ) has been shown to own promising potential in clinically combating SARS-CoV-2 but the underlying mechanisms remain highly elusive and its action sites were proposed all on the host cells. Very recently, by NMR spectroscopy, for the first time we have decoded that HCQ specifically binds 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 final package of gRNA and N protein into new virions. Here with NMR-derived constraints, we constructed the structure of the HCQ-CTD complex in which HCQ binds two pockets on the dimeric CTD. This unexpected finding thus allowed us to formulate a design strategy by linking two HCQ together to generate a bivalent/multivalent binder for CTD. The linked molecule is anticipated to have significantly enhanced affinity and specificity in binding CTD. We are willing to collaborate with synthetic chemists on this strategy by experimentally charactering the synthetic molecules on their binding and effects on LLPS of SARS-CoV-2 N protein.
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