Harnessing Membrane-Active Peptides for Selective Cancer Targeting: Phosphatidylserine Recognition by Tilapia Piscidin 4
Year: 2026
Type: article
Abstract: Membrane-active peptides (MAPs) have garnered significant attention as potential alternatives to conventional cancer therapies, which are frequently limited by severe side effects. Among them, antimicrobial peptides (AMPs) that leverage differences between the plasma membranes of cancer cells and healthy cells are particularly attractive. While several AMPs have demonstrated anticancer potency, structure-function relationship studies are lacking to explain the molecular basis of their selectivity and to help design improved analogs. Here, we contribute to filling this gap by investigating Nile tilapia piscidin 4 (TP4), an AMP with demonstrated activity against several solid organ cancers. First, we discover through biological assays that the anticancer activity of the peptide, which underscores a promising therapeutic window, is associated with increased plasma membrane permeability in cancer cells compared to normal cells and positively (negatively) correlated with enzymes that enrich (deplete) anionic PS in the outer leaflet. Next, we utilize a suite of complementary techniques on model membranes to investigate the interactions of TP4 with membranes, uncovering behaviors not previously observed in related AMPs. Circular dichroism experiments reveal that TP4 preferentially binds to zwitterionic phosphatidylcholine (PC) membranes enriched in anionic PS, while cholesterol markedly impairs binding. X-ray diffraction demonstrates that TP4 disrupts PC-PS membranes by inducing lipid segregation. Covering a range of biologically relevant peptide concentrations with neutron diffraction and reflectometry measurements in fluid bilayers and MD simulations, we unveil how TP4 and associated water gradually insert into the hydrocarbon region and cause convoluted membrane deformations to breach the membrane barriers. These studies highlight the pivotal role of the TP4 polyarginine tail in driving selective membrane binding and disruption on membranes enriched with the anionic lipid PS. Together, our results elucidate the molecular determinants underpinning the selective anticancer effects of TP4, providing a strategic framework for the rational design of advanced membrane-active therapeutics.
Source: JACS Au
Language: English
Subfield: Microbiology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funders: Center for Cancer Research, U.S. Department of Energy, U.S. Department of Health and Human Services, U.S. Department of Commerce, National Institutes of Health, National Institute of Standards and Technology, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, Basic Energy Sciences, NIST Center for Neutron Research, Oak Ridge National Laboratory
Awards: G234904543, G4135575038, Mechanistic Investigations of Host Defense Metallopeptide Interactions with Bacterial Cell Membranes, G5263496603, G7349965092, PURPOSE: THE PURPOSE OF THIS GRANT IS TO ADVANCE NEUTRON-BASED MEASUREMENTS TO SUPPORT KEY INDUSTRIES OF THE US ECONOMY. TO SUPPORT THE PROPOSED COLLABORATION TO MEET EXISTING AND EMERGING NEEDS OF STAKEHOLDERS IN BIOTECHNOLOGY AND BIOMANUFACTURING.ACTIVITIES TO BE PERFORMED: DEVELOPMENT IN SAMPLE PREPARATION AND ANALYSIS, AS WELL AS CUTTING-EDGE AND VITAL FUNDAMENTAL RESEARCH PROBLEMS THAT MUST BE ADDRESSED IN BIOTECHNOLOGY AND BIOMANUFACTURING. THIS WILL IMPACT NOVICE USERS OF NEUTRON SCATTERING WHILE AT THE SAME TIME CREATING INNOVATIVE MEASUREMENT AND ANALYSIS MODALITIES FOR FUTURE APPLICATIONS. EXPAND THE RESEARCH PROGRAMS IN NEUTRONS AND, SEPARATELY, ARTIFICIAL INTELLIGENCE AND PROVIDE NEW EDUCATIONAL OPPORTUNITIES TO UNDERGRADUATE, GRADUATE, AND POST-GRADUATE STUDENTS OF CARNEGIE MELLON.EXPECTED OUTCOMES: INNOVATIONS IN SAMPLE PREPARATION AND ANALYSIS, AS WELL AS CUTTING-EDGE AND VITAL FUNDAMENTAL RESEARCH PROBLEMS. THIS WILL IMPACT NOVICE USERS OF NEUTRON SCATTERING WHILE AT THE SAME TIME CREATING INNOVATIVE MEASUREMENT AND ANALYSIS MODALITIES FOR FUTURE APPLICATIONS.INTENDED BENEFICIARIES: CARNEGIE MELLON UNIVERSITY WILL BENEFIT BY ADVANCED SCIENTIFIC CAPACITY TO BETTER EDUCATE STUDENTS AND ADVANCE SCIENCE THROUGH INSTRUMENT DEVELOPMENT PROJECTS. THE GENERAL PUBLIC BY GAINING ACCESS TO STATE-OF-THE-ART MEASUREMENT TECHNIQUES THROUGH THE NCNR GENERAL USER PROGRAM AND NEW THERAPEUTICS THAT ARE ANTICIPATED TO RESULT FROM THESE CAPABILITIES.SUBRECIPIENT ACTIVITIES: THE RECIPIENT DOES NOT INTEND TO SUBAWARD FUNDS., G9000190187
OpenAlex ID: W7151491491