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.
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DOI：
10.1016/j.antiviral.2020.104922
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发表时间：
2020-08
影响因子：
7.6
通讯作者：
Zhiqiang Xia;Luyao Wang;Songryong Li;Wei-Feng Tang;F. Sun;Yingliang Wu;Lixia Miao;Zhijian Cao
中科院分区：
文献类型：
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作者：
Zhiqiang Xia;Luyao Wang;Songryong Li;Wei-Feng Tang;F. Sun;Yingliang Wu;Lixia Miao;Zhijian Cao
虫媒病毒，特别是登革病毒（DENV）和寨卡病毒（ZIKV），由于无法控制的传播，在过去几年中已严重威胁人类健康。目前还没有批准的疫苗或临床药物可用于预防和治疗他们的感染。瞬时受体电位粘脂蛋白2和3（TRPML 2和TRPML 3）被报道调节病毒进入，但这些调节剂的抗病毒功能是未知的。在这里，我们报道了TRPML激动剂ML-SA 1以剂量依赖性方式抑制DENV 2和ZIKVin体外。加药时间实验表明，ML-SA 1主要限制病毒进入。此外，发现选择性TRPML 3激活剂SN-2对DENV 2和ZIKV具有相似的抗病毒作用，但特异性TRPML 1激动剂MK 6 -83无效。虽然ML-SA 1进一步揭示了诱导自噬，但其抗病毒作用不依赖于自噬诱导。最后，发现ML-SA 1通过促进溶酶体酸化和蛋白酶活性以引起病毒降解来抑制DENV 2和ZIKV。总之，我们的研究确定了两种TRPML激动剂ML-SA 1和SN-2作为DENV 2和ZIKV的有效抑制剂，这可能导致发现新的抗病毒候选物。
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 ZIKVin vitroin 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.