Targeting the N-Terminus Domain of the Coronavirus Nucleocapsid Protein Induces Abnormal Oligomerization via Allosteric Modulation.

Autor:	Hsu JN; Institute of Genomics and Bioinformatics and Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan., Chen JS; Department of Chemistry, National Chung Hsing University, Taichung, Taiwan., Lin SM; Institute of Genomics and Bioinformatics and Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan., Hong JY; Institute of Genomics and Bioinformatics and Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan., Chen YJ; Department of Chemistry, National Chung Hsing University, Taichung, Taiwan., Jeng US; National Synchrotron Radiation Research Center, Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan., Luo SY; Department of Chemistry, National Chung Hsing University, Taichung, Taiwan., Hou MH; Institute of Genomics and Bioinformatics and Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular biosciences [Front Mol Biosci] 2022 Apr 19; Vol. 9, pp. 871499. Date of Electronic Publication: 2022 Apr 19 (Print Publication: 2022).
DOI:	10.3389/fmolb.2022.871499
Abstrakt:	Epidemics caused by coronaviruses (CoVs), namely the severe acute respiratory syndrome (SARS) (2003), Middle East respiratory syndrome (MERS) (2012), and coronavirus disease 2019 (COVID-19) (2019), have triggered a global public health emergency. Drug development against CoVs is inherently arduous. The nucleocapsid (N) protein forms an oligomer and facilitates binding with the viral RNA genome, which is critical in the life cycle of the virus. In the current study, we found a potential allosteric site (Site 1) using PARS, an online allosteric site predictor, in the CoV N-N-terminal RNA-binding domain (NTD) to modulate the N protein conformation. We identified 5-hydroxyindole as the lead via molecular docking to target Site 1. We designed and synthesized four 5-hydroxyindole derivatives, named P4-1 to P4-4, based on the pose of 5-hydroxyindole in the docking model complex. Small-angle X-ray scattering (SAXS) data indicate that two 5-hydroxyindole compounds with higher hydrophobic R-groups mediate the binding between N-NTD and N-C-terminal dimerization domain (CTD) and elicit high-order oligomerization of the whole N protein. Furthermore, the crystal structures suggested that these two compounds act on this novel cavity and create a flat surface with higher hydrophobicity, which may mediate the interaction between N-NTD and N-CTD. Taken together, we discovered an allosteric binding pocket targeting small molecules that induces abnormal aggregation of the CoV N protein. These novel concepts will facilitate protein-protein interaction (PPI)-based drug design against various CoVs. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Hsu, Chen, Lin, Hong, Chen, Jeng, Luo and Hou.)
Databáze:	MEDLINE
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