Research reveals the assembly dynamics of nucleocapsid protein condensates can be regulated by small molecules with therapeutic potential biorxivpreprint harvardmed Harvard virus coronavirus humancoronaviruses protein nucleocapsidprotein
By Tarun Sai LomteDec 12 2022Reviewed by Danielle Ellis, B.Sc. In a recent study posted to bioRxiv*, researchers developed a screening platform and identified molecules with anti-coronavirus activity.
Lately, studies have identified small molecules modulating the phase transition of proteins involved in respiratory syncytial virus infection and amyotrophic lateral sclerosis . This has increased interest in targeting condensates for drug discovery; however, only a few molecules have been identified.
PolyIC-induced nucleocapsid condensates of SARS-CoV-2, SARS-CoV-2, MERS-CoV, and HCoV-HKU1 were much more dynamic than constitutive condensates. Next, the team speculated that small molecules that can modulate the phase behavior of nucleocapsid condensates would exert antiviral functions. Loss- and gain-of-function experiments were performed to test whether GSK3 was indeed the target of pro-condensers. Robust condensation of SARS-CoV-2 nucleocapsid was evident upon stimulating cells with a ligand that activates Wnt signaling, leading to the inhibition of GSK3. Likewise, the effect of inhibitors was recapitulated after knocking out GSK3α or GSK3β. Double knockout had a more potent effect than single knockouts of either GS kinase.
Thus, separating the risk of activating Wnt signaling with the modulation of SARS-CoV-2 nucleocapsid condensation would be difficult. On the other hand, the therapeutic modulation of nucleocapsid might be viable for HCoVs such as NL63 and HKU1, where exposure to drugs below the threshold for Wnt signaling activation might be anti-viral.
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