{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T21:00:06Z","timestamp":1788642006384,"version":"build-2803163510"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Fund of China","doi-asserted-by":"publisher","award":["32561160088"],"award-info":[{"award-number":["32561160088"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Fund of China","doi-asserted-by":"publisher","award":["32370547"],"award-info":[{"award-number":["32370547"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Fund of China","doi-asserted-by":"publisher","award":["32570597"],"award-info":[{"award-number":["32570597"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFF1304900"],"award-info":[{"award-number":["2023YFF1304900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Research and Development and Promotion of Special Scientific and Technological Projects in Henan Province","award":["252102311225"],"award-info":[{"award-number":["252102311225"]}]},{"name":"Science and Technology Research Project in the Social Development Field of Zhumadian City","award":["ZMDSKJGG2025014"],"award-info":[{"award-number":["ZMDSKJGG2025014"]}]},{"name":"Science and Technology Research Project in the Social Development Field of Zhumadian City","award":["ZMDSKJGG2025023"],"award-info":[{"award-number":["ZMDSKJGG2025023"]}]},{"name":"Innovative Research Group of Hubei Natural Science Foundation","award":["2025AFA017"],"award-info":[{"award-number":["2025AFA017"]}]},{"name":"Green Science and Technology Leading Program Project from Hubei University of Technology","award":["XJ2024000201"],"award-info":[{"award-number":["XJ2024000201"]}]},{"name":"Green Science and Technology Leading Program Project from Hubei University of Technology","award":["GCC2024009"],"award-info":[{"award-number":["GCC2024009"]}]},{"name":"Science and Technology Development Fund of Macau S.A.R.","award":["0069\/2025\/AFJ"],"award-info":[{"award-number":["0069\/2025\/AFJ"]}]},{"name":"University of Macau (UM)\u2014Dr Stanley Ho Medical Development Foundation","award":["SHMDF-VSEP\/2024\/002"],"award-info":[{"award-number":["SHMDF-VSEP\/2024\/002"]}]},{"name":"UM Multi-Year Research Grant General Research Grant","award":["MYRG-GRG-2025-0067-FHS"],"award-info":[{"award-number":["MYRG-GRG-2025-0067-FHS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>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\u2014MMTX, BmP05, BmTX1, and BmKK12\u2014were 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.<\/jats:p>","DOI":"10.3390\/toxins18020110","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T15:57:11Z","timestamp":1771603031000},"page":"110","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Discovery of Two Novel Scorpion Venom Peptides Activating TRPML2 to Impair ZIKV Internalization"],"prefix":"10.3390","volume":"18","author":[{"given":"Zhiqiang","family":"Xia","sequence":"first","affiliation":[{"name":"School of Biological and Food Processing Engineering, Huanghuai University, Zhumadian 463000, China"},{"name":"National \u201c111\u201d Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), School of Life and Health Sciences, Hubei University of Technology, Wuhan 430086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhua","family":"Yang","sequence":"additional","affiliation":[{"name":"National \u201c111\u201d Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), School of Life and Health Sciences, Hubei University of Technology, Wuhan 430086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dangui","family":"He","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayuan","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Biological and Food Processing Engineering, Huanghuai University, Zhumadian 463000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixia","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Biological and Food Processing Engineering, Huanghuai University, Zhumadian 463000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Biological and Food Processing Engineering, Huanghuai University, Zhumadian 463000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahuan","family":"Jin","sequence":"additional","affiliation":[{"name":"School of Biological and Food Processing Engineering, Huanghuai University, Zhumadian 463000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Li","sequence":"additional","affiliation":[{"name":"Zhumadian Huazhong Chia Tai Co., Ltd., Zhumadian 463000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1332-8895","authenticated-orcid":false,"given":"Alexandre K.","family":"Tashima","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Paulista School of Medicine, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04023-062, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6349-4517","authenticated-orcid":false,"given":"Hang Fai","family":"Kwok","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijian","family":"Cao","sequence":"additional","affiliation":[{"name":"National \u201c111\u201d Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), School of Life and Health Sciences, Hubei University of Technology, Wuhan 430086, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41392-023-01464-x","article-title":"TRP (transient receptor potential) ion channel family: Structures, biological functions and therapeutic interventions for diseases","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct. 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