Discovery of Two Novel Scorpion Venom Peptides Activating TRPML2 to Impair ZIKV Internalization
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.
Xia Z, Yang X, He D, Chang J, Xie L, Liu Q, Jin J, Li B, Tashima AK, Kwok HF, et al. Discovery of Two Novel Scorpion Venom Peptides Activating TRPML2 to Impair ZIKV Internalization. Toxins. 2026; 18(2):110. https://doi.org/10.3390/toxins18020110
