Browsing by Author "Zhong, Wu"

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    Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives
    (Elsevier, 2018-09) Tao, Zeyu; Cao, Ruiyuan; Yan, Yunzheng; Huang, Guocheng; Lv, Kai; Li, Wei; Geng, Yunhe; Zhao, Lei; Wang, Apeng; He, Qinhao; Yang, Jingjing; Fan, Shiyong; Huang, Menghao; Guo, Huiyuan; Zhong, Wu; Lu, Mingliang; Medicine, School of Medicine
    We report herein the design and synthesis of a series of novel Sinefungin (SIN) derivatives, based on the structures of SIN and its analogue EPZ004777. Our results reveal that target compounds 1ad-af, 1ba-bb and 1bf-bh show better activity (IC50 = 4.56–20.16 μM) than EPZ004777 (IC50 = 35.19 μM). Surprisingly, SIN was founded to be not as active (IC50 > 50 μM) as we and other research groups predicted. Interestingly, the intermediates 9a-b and 11b display potent anti-ZIKV potency (IC50 = 6.33–29.98 μM), and compound 9a also exhibits acceptable cytotoxicity (CC50 > 200 μM), suggesting their promising potential to be leads for further development.
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    In vitro and in vivo inhibition of the host TRPC4 channel attenuates Zika virus infection
    (EMBO Press, 2024) Chen, Xingjuan; Yan, Yunzheng; Liu, Zhiqiang; Yang, Shaokang; Li, Wei; Wang, Zhuang; Wang, Mengyuan; Guo, Juan; Li, Zhenyang; Zhu, Weiyan; Yang, Jingjing; Yin, Jiye; Dai, Qingsong; Li, Yuexiang; Wang, Cui; Zhao, Lei; Yang, Xiaotong; Guo, Xiaojia; Leng, Ling; Xu, Jiaxi; Obukhov, Alexander G.; Cao, Ruiyuan; Zhong, Wu; Anatomy, Cell Biology and Physiology, School of Medicine
    Zika virus (ZIKV) infection may lead to severe neurological consequences, including seizures, and early infancy death. However, the involved mechanisms are still largely unknown. TRPC channels play an important role in regulating nervous system excitability and are implicated in seizure development. We investigated whether TRPCs might be involved in the pathogenesis of ZIKV infection. We found that ZIKV infection increases TRPC4 expression in host cells via the interaction between the ZIKV-NS3 protein and CaMKII, enhancing TRPC4-mediated calcium influx. Pharmacological inhibition of CaMKII decreased both pCREB and TRPC4 protein levels, whereas the suppression of either TRPC4 or CaMKII improved the survival rate of ZIKV-infected cells and reduced viral protein production, likely by impeding the replication phase of the viral life cycle. TRPC4 or CaMKII inhibitors also reduced seizures and increased the survival of ZIKV-infected neonatal mice and blocked the spread of ZIKV in brain organoids derived from human-induced pluripotent stem cells. These findings suggest that targeting CaMKII or TRPC4 may offer a promising approach for developing novel anti-ZIKV therapies, capable of preventing ZIKV-associated seizures and death.