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Structural and Functional Characterizations of Flavivirus NS5: Perspective for Drug Discovery and Vaccine Development


Flaviviruses have historically caused severe epidemics or pandemics, but few therapies are available currently. NS5 is a critical enzyme responsible for fiaviviral life cycle, and suppresses host immune response via host-pathogen interaction as well. In this study, we determined the crystal structure of Zika virus (ZIKV), a member of flavivirus family, revealing flavivirus NS5 proteins share a conserved domain conformation. A small molecule inhibitor, I29, was subsequently proved to bind to ZIKV NS5. Meanwhile, we solved the structure of ZIKV NS5 in complex with its host partner, human STAT2 (hSTAT2), suggesting a bypass pathway to interfere immune response. We were able to rescue viral strains with mutations of residues involved in hSTAT2-binding, providing novel insights into vaccine development.

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