# Discovery of Two Novel Scorpion Venom Peptides Activating TRPML2 to Impair ZIKV Internalization

## TL;DR

Researchers discovered two scorpion venom peptides that activate a cellular channel to block Zika virus entry, offering new tools for studying cell biology and developing antiviral treatments.

## Contribution

First report of animal venom-derived peptides acting as specific TRPML2 agonists with antiviral activity against ZIKV.

## Key findings

- BmP05 and BmKK12 peptides strongly activate TRPML2 and increase Ca2+ influx.
- BmP05 and BmKK12 inhibit ZIKV replication at non-cytotoxic concentrations.
- Peptides MMTX and BmTX1 showed weaker or no antiviral effects.

## Abstract

The endo-lysosomal channel TRPML2 regulates key processes like membrane trafficking and autophagy, which are hijacked by many RNA viruses during endocytic entry. However, the development of TRPML2-targeted therapeutics has been hindered by a notable lack of high-affinity and selective peptide-based activators. Scorpion venom peptides, honed by evolution for exceptional specificity toward diverse membrane ion channels, represent a promising, underexplored natural library for discovering novel pharmacological probes and drug leads. Here, we screened and identified seven candidate peptides interacting with TRPML2 using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of the Mesobuthus martensii venom. Based on molecular docking analysis, the top four candidates—MMTX, BmP05, BmTX1, and BmKK12—were selected for chemical synthesis, oxidatively cyclized to form their native disulfide-bridged conformations, and subsequently purified and characterized by analytical HPLC and MS. Calcium imaging confirmed that two of the four oxidized peptides, BmP05 and BmKK12, exhibited superior potency in inducing a sharp increase in Ca2+ influx. Crucially, BmP05 and BmKK12 demonstrated potent, concentration-dependent inhibition of Zika virus (ZIKV) replication at the RNA level at non-cytotoxic concentrations, whereas the weaker activators MMTX and BmTX1 did not. The current study first reports animal venom-derived peptides that function as specific TRPML2 agonists with concomitant antiviral activity. Together, our findings provide not only new molecular probes for dissecting TRPML2 biology but also a pioneering strategy for developing host-directed, broad-spectrum therapeutics against viruses dependent on endo-lysosomal entry.