2. Academic Validation
  3. ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity

ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity

  • Antiviral Res. 2020 Oct;182:104922. doi: 10.1016/j.antiviral.2020.104922.
Zhiqiang Xia 1,  Luyao Wang 1,  Songryong Li 1,  Wei Tang 1,  Fang Sun 1,  Yingliang Wu 2,  Lixia Miao 3,  Zhijian Cao 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 2 State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, 430072, China; Bio-drug Research Center, Wuhan University, Wuhan, 430072, China.
  • 3 Department of Biochemistry, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China. Electronic address: miaolixia@whu.edu.cn.
  • 4 State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, 430072, China; Bio-drug Research Center, Wuhan University, Wuhan, 430072, China; Hubei Province Engineering and Technology Research, Center for Fluorinated Pharmaceuticals, Wuhan University, Wuhan, 430072, China. Electronic address: zjcao@whu.edu.cn.
PMID: 32858116 DOI: 10.1016/j.antiviral.2020.104922
Abstract

Arboviruses, especially Dengue virus (DENV) and Zika virus (ZIKV), have been a severe threat to human health in the last few years due to uncontrollable transmission. There are no approved vaccines or clinical drugs available for use to prevent and treat their infections. Transient receptor potential mucolipin 2 and 3 (TRPML2 and TRPML3) were reported to modulate viral entry, but the Antiviral function of these modulators was unknown. Here, we reported that ML-SA1, a TRPML agonist, inhibited DENV2 and ZIKV in vitro in a dose-dependent manner. Time-of-drug-addition experiments showed that ML-SA1 mainly restricted viral entry. Moreover, the selective TRPML3 activator SN-2 was found to share a similar Antiviral effect against DENV2 and ZIKV, but the specific TRPML1 agonist MK6-83 was not effective. Although ML-SA1 was further revealed to induce Autophagy, its Antiviral role was independent of Autophagy induction. Finally, ML-SA1 was found to inhibit DENV2 and ZIKV by promoting lysosome acidification and Protease activity to cause viral degradation. Together, our study identifies two TRPML agonists, ML-SA1 and SN-2, as potent inhibitors of DENV2 and ZIKV, which may lead to the discovery of new candidates against viruses.

Keywords

Agonist; Autophagy; DENV2; Lysosomal acidification; TRPML; ZIKV.

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