ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity
Autor: | Wei Tang, Fang Sun, Luyao Wang, Yingliang Wu, Zhiqiang Xia, Songryong Li, Zhijian Cao, Lixia Miao |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Agonist Carcinoma Hepatocellular TRPML medicine.drug_class medicine.medical_treatment 030106 microbiology Phthalimides Biology Dengue virus medicine.disease_cause Antiviral Agents 03 medical and health sciences Transient receptor potential channel Transient Receptor Potential Channels Viral entry Cell Line Tumor Virology Lysosome Autophagy medicine Humans Pharmacology Protease Zika Virus Infection Liver Neoplasms Zika Virus Dengue Virus Hydrogen-Ion Concentration 030104 developmental biology medicine.anatomical_structure A549 Cells Proteolysis Quinolines Lysosomes Peptide Hydrolases |
Zdroj: | Antiviral Research. 182:104922 |
ISSN: | 0166-3542 |
Popis: | 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. |
Databáze: | OpenAIRE |
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