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ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity
Zhiqiang Xia1, Luyao Wang1, Songryong Li1
1State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
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.
Insights
ML-SA1 and SN-2, TRPML agonists, effectively inhibit Dengue virus (DENV) and Zika virus (ZIKV) by promoting lysosome acidification and protease activity, offering potential new antiviral therapies.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Arboviruses like Dengue virus (DENV) and Zika virus (ZIKV) pose significant global health threats.
- Current treatments lack approved vaccines or clinical drugs for DENV and ZIKV infections.
- Transient receptor potential mucolipin (TRPML) channels' role in viral entry modulation was known, but their antiviral function remained unclear.
Purpose of the Study:
- To investigate the antiviral potential of TRPML agonists against DENV and ZIKV.
- To elucidate the mechanism of action for TRPML agonists in inhibiting viral replication.
- To identify novel therapeutic candidates for arbovirus infections.
Main Methods:
- In vitro antiviral assays using DENV2 and ZIKV.
- Time-of-drug-addition experiments to determine the stage of viral inhibition.
- Utilizing selective TRPML channel activators (ML-SA1, SN-2, MK6-83).
- Autophagy induction assays.
- Analysis of lysosome acidification and protease activity.
Main Results:
- ML-SA1 demonstrated dose-dependent inhibition of DENV2 and ZIKV replication in vitro.
- ML-SA1 primarily restricted viral entry, independent of autophagy induction.
- The selective TRPML3 activator SN-2 exhibited similar antiviral effects against DENV2 and ZIKV.
- The TRPML1 agonist MK6-83 showed no significant antiviral activity.
- ML-SA1 inhibited DENV2 and ZIKV by enhancing lysosome acidification and protease activity, leading to viral degradation.
Conclusions:
- ML-SA1 and SN-2 are potent inhibitors of DENV2 and ZIKV.
- TRPML channel activation, particularly TRPML3, offers a promising strategy for arbovirus control.
- The mechanism involves enhanced lysosomal function, suggesting a novel therapeutic pathway.
- These findings pave the way for developing new antiviral drug candidates against DENV and ZIKV.
