{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T02:55:25Z","timestamp":1792292125391,"version":"4.4.0"},"reference-count":46,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T00:00:00Z","timestamp":1759363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"S\u00e3o Paulo Research Foundation (FAPESP), Brazil","award":["2022\/07231-7"],"award-info":[{"award-number":["2022\/07231-7"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Polybia-MP1 (MP1) exhibits antimicrobial and anticancer properties. To improve selectivity toward acidic tumor microenvironments, we designed HMP1, a histidine-substituted analog of MP1, aiming to introduce pH-responsive behavior within physiological and pathological pH ranges. Methods: HMP1 was synthesized by replacing all lysine residues in MP1 with histidines. We characterized its surfactant properties and interactions with lipid monolayers composed of DPPC under varying pH and ionic strength conditions. Langmuir monolayer experiments were used to evaluate peptide-induced morphological changes and lipid packing effects at physiologically relevant lateral pressures. Results: HMP1 displayed pH-dependent activity between pH 5.5 and 7.5, inducing significant morphological reorganization of lipid domains without reducing the condensed phase area. Ionic strength modulated these effects, with distinct behaviors observed at low and physiological saline conditions. HMP1 preferentially interacted with cholesterol-enriched membranes, while MP1 did not induce comparable effects under the same conditions, as previously reported, at physiological lateral pressures. HMP1 also exhibited non-hemolytic properties and lower cytotoxicity compared to MP1. Conclusions: The lysine-to-histidine substitution conferred pH sensitivity to HMP1, enabling selective modulation of membrane organization based on lipid composition, packing, pH, and ionic environment. These findings highlight HMP1\u2019s potential in targeted therapeutics and pH-responsive drug delivery systems.<\/jats:p>","DOI":"10.3390\/pharmaceutics17101287","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T08:20:28Z","timestamp":1759393228000},"page":"1287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Tweaking Polybia-MP1: How a Lysine-Histidine Swap Redefines Its Surface Properties"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7190-9148","authenticated-orcid":false,"given":"Kenneth M. F.","family":"Miasaki","sequence":"first","affiliation":[{"name":"Department of Physics, IBILCE, UNESP\u2014S\u00e3o Paulo State University, S\u00e3o Jos\u00e9 do Rio Preto 15054-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4355-2361","authenticated-orcid":false,"given":"Bibiana M.","family":"Souza","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Biology, Institute of Biosciences, UNESP\u2014S\u00e3o Paulo State University, Rio Claro 13506-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7363-8211","authenticated-orcid":false,"given":"Mario S.","family":"Palma","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Biology, Institute of Biosciences, UNESP\u2014S\u00e3o Paulo State University, Rio Claro 13506-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2342-0193","authenticated-orcid":false,"given":"Natalia","family":"Wilke","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones en Qu\u00edmica Biol\u00f3gica de C\u00f3rdoba (CIQUIBIC), CONICET, Haya de la Torre y Medina Allende, Ciudad Universitaria, C\u00f3rdoba X5000HUA, Argentina"},{"name":"Departamento de Qu\u00edmica Biol\u00f3gica Ranwel Caputto, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba X5000HUA, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2283-3316","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Ruggiero Neto","sequence":"additional","affiliation":[{"name":"Department of Physics, IBILCE, UNESP\u2014S\u00e3o Paulo State University, S\u00e3o Jos\u00e9 do Rio Preto 15054-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6521-9148","authenticated-orcid":false,"given":"Dayane S.","family":"Alvares","sequence":"additional","affiliation":[{"name":"Department of Physics, IBILCE, UNESP\u2014S\u00e3o Paulo State University, S\u00e3o Jos\u00e9 do Rio Preto 15054-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/415389a","article-title":"Antimicrobial peptides of multicellular organisms","volume":"415","author":"Zasloff","year":"2002","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s10989-023-10543-0","article-title":"Why to study peptides from venomous and poisonous animals?","volume":"29","author":"Soares","year":"2023","journal-title":"Int. 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