{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T03:49:00Z","timestamp":1777952940530,"version":"3.51.4"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:p>Peptide lipidation is widely employed to enhance the apparent biological performance of peptide-based systems by improving stability, membrane association, and systemic persistence. However, increased potency is often interpreted uncritically as evidence of improved molecular design. This Perspective highlights that lipidation can reshape peptide behaviour by partially shifting functional control from sequence-encoded molecular recognition toward context-dependent effects in which membrane interactions, carrier binding, supramolecular assembly, and residence time play an increasingly important role. Under such design-dependent conditions, enhanced activity may primarily reflect delivery- and exposure-driven amplification rather than improved intrinsic efficacy. While MIC values and endpoint assays remain valuable benchmarks of activity, they are insufficient on their own to guide rational optimization of lipidated peptides, as they conflate intrinsic activity with lipid-driven distribution and time-dependent effects. Accordingly, this Perspective argues not against lipidation itself, but for reframing lipidation as a deliberately controllable interaction element rather than a generic potency modifier, thereby restoring mechanistic interpretability and design robustness in peptide chemical biology.<\/jats:p>","DOI":"10.3389\/fchem.2026.1807712","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T13:42:25Z","timestamp":1777902145000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Lipidated peptides and the limits of chemical control"],"prefix":"10.3389","volume":"14","author":[{"given":"Cesar Augusto","family":"Roque-Borda","sequence":"first","affiliation":[{"name":"Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda de Arequipa","place":["Arequipa, Peru"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anamika","family":"Sharma","sequence":"additional","affiliation":[{"name":"Peptide Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal","place":["Durban, South Africa"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando Rog\u00e9rio","family":"Pavan","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Laboratory, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP)","place":["Araraquara, Brazil"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz G.","family":"de la Torre","sequence":"additional","affiliation":[{"name":"Peptide Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal","place":["Durban, South Africa"]},{"name":"School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal","place":["Durban, South Africa"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Albericio","sequence":"additional","affiliation":[{"name":"Peptide Science Laboratory, School of Chemistry and Physics, University of KwaZulu-Natal","place":["Durban, South Africa"]},{"name":"Department of Inorganic and Organic Chemistry, University of Barcelona","place":["Barcelona, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1021\/acs.biomac.3c01184","article-title":"Self-assembly and antimicrobial activity of lipopeptides containing lysine-rich tripeptides","volume":"25","author":"Adak","year":"2024","journal-title":"Biomacromolecules"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2216","DOI":"10.1016\/j.bbamem.2014.04.014","article-title":"Membrane-active peptides: binding, translocation, and flux in lipid vesicles","volume":"1838","author":"Almeida","year":"2014","journal-title":"Biochimica Biophysica Acta (BBA) - Biomembr."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2446","DOI":"10.1021\/acs.jpcb.4c05019","article-title":"Strong membrane permeabilization activity can reduce selectivity of cyclic antimicrobial peptides","volume":"129","author":"Beck","year":"2025","journal-title":"J. Phys. Chem. B"},{"key":"B4","doi-asserted-by":"publisher","first-page":"439","DOI":"10.3390\/ph16030439","article-title":"Glycosylation and lipidation strategies: approaches for improving antimicrobial peptide efficacy","volume":"16","author":"Bellavita","year":"2023","journal-title":"Pharmaceuticals"},{"key":"B5","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1007\/s12551-025-01312-y","article-title":"Unlocking the power of membrane biophysics: enhancing the study of antimicrobial peptides activity and selectivity","volume":"17","author":"Bertrand","year":"2025","journal-title":"Biophys. Rev."},{"key":"B6","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1038\/s42003-018-0230-4","article-title":"Antibacterial isoamphipathic oligomers highlight the importance of multimeric lipid aggregation for antibacterial potency","volume":"1","author":"Brown","year":"2018","journal-title":"Commun. Biol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1111\/1751-7915.14213","article-title":"Structure\u2013activity relationships of antibacterial peptides","volume":"16","author":"Ciulla","year":"2023","journal-title":"Microb. Biotechnol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/nnano.2010.29","article-title":"Kinetics of antimicrobial peptide activity measured on individual bacterial cells using high-speed atomic force microscopy","volume":"5","author":"Fantner","year":"2010","journal-title":"Nat. Nanotechnol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1208\/s12248-014-9681-9","article-title":"Early engineering approaches to improve peptide developability and manufacturability","volume":"17","author":"Furman","year":"2015","journal-title":"AAPS J."},{"key":"B10","doi-asserted-by":"publisher","first-page":"6341","DOI":"10.1021\/cr2001977","article-title":"Exploring protein lipidation with chemical biology","volume":"111","author":"Hang","year":"2011","journal-title":"Chem. Rev."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1942","DOI":"10.1021\/acs.jmedchem.5c02390","article-title":"Fatty acid-conjugated antimicrobial peptides: advances in design, activity, and therapeutic potential","volume":"69","author":"Helmy","year":"2026","journal-title":"J. Med. Chem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1002\/psc.2954","article-title":"Peptide hormones and lipopeptides: from self\u2010assembly to therapeutic applications","volume":"23","author":"Hutchinson","year":"2017","journal-title":"J. Peptide Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1021\/acs.chemrev.6b00750","article-title":"Protein lipidation: occurrence, mechanisms, biological functions, and enabling technologies","volume":"118","author":"Jiang","year":"2018","journal-title":"Chem. Rev."},{"key":"B14","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1039\/D0FD00041H","article-title":"Antimicrobial peptides: mechanism of action and lipid-mediated synergistic interactions within membranes","volume":"232","author":"Juhl","year":"2021","journal-title":"Faraday Discuss."},{"key":"B15","doi-asserted-by":"publisher","first-page":"4103","DOI":"10.1111\/bph.16104","article-title":"The importance of binding kinetics and drug\u2013target residence time in pharmacology","volume":"181","author":"Knockenhauer","year":"2024","journal-title":"Br. J. Pharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1021\/jm9909645","article-title":"Potent derivatives of glucagon-like Peptide-1 with pharmacokinetic properties suitable for once daily administration","volume":"43","author":"Knudsen","year":"2000","journal-title":"J. Med. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"100962","DOI":"10.1016\/j.neo.2023.100962","article-title":"Impact of tissue penetration and albumin binding on design of T cell targeted bispecific agents","volume":"48","author":"Kopp","year":"2024","journal-title":"Neoplasia"},{"key":"B18","first-page":"185","volume-title":"Peptide lipidation \u2013 a synthetic strategy to afford peptide based therapeutics","author":"Kowalczyk","year":"2017"},{"key":"B19","doi-asserted-by":"publisher","first-page":"999","DOI":"10.2337\/diabetes.49.6.999","article-title":"Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use","volume":"49","author":"Kurtzhals","year":"2000","journal-title":"Diabetes"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1074359","DOI":"10.3389\/fmicb.2022.1074359","article-title":"Designing double-site lipidated peptide amphiphiles as potent antimicrobial biomaterials to combat multidrug-resistant bacteria","volume":"13","author":"Lai","year":"2022","journal-title":"Front. Microbiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"3331","DOI":"10.1038\/s41598-019-39219-w","article-title":"Cationic intrinsically disordered antimicrobial peptides (CIDAMPs) represent a new paradigm of innate defense with a potential for novel anti-infectives","volume":"9","author":"Latendorf","year":"2019","journal-title":"Sci. Rep."},{"key":"B22","doi-asserted-by":"publisher","first-page":"7370","DOI":"10.1021\/acs.jmedchem.5b00726","article-title":"Discovery of the once-weekly glucagon-like Peptide-1 (GLP-1) analogue semaglutide","volume":"58","author":"Lau","year":"2015","journal-title":"J. Med. Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e329","DOI":"10.1002\/agt2.329","article-title":"The effect of tailing lipidation on the bioactivity of antimicrobial peptides and their aggregation tendency","volume":"4","author":"Lin","year":"2023","journal-title":"Aggregate"},{"key":"B24","doi-asserted-by":"publisher","first-page":"118264","DOI":"10.1016\/j.biopha.2025.118264","article-title":"Optimized strategies for designing antimicrobial peptides targeting multidrug-resistant Gram-negative bacteria","volume":"189","author":"Liu","year":"2025","journal-title":"Biomed. and Pharmacother."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e2014364118","DOI":"10.1073\/pnas.2014364118","article-title":"Inoculum effect of antimicrobial peptides","volume":"118","author":"Loffredo","year":"2021","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"10630","DOI":"10.1021\/bi8011675","article-title":"Antimicrobial lipopolypeptides composed of palmitoyl Di- and tricationic peptides: in vitro and in vivo activities, self-assembly to nanostructures, and a plausible mode of action","volume":"47","author":"Makovitzki","year":"2008","journal-title":"Biochemistry"},{"key":"B27","doi-asserted-by":"publisher","first-page":"3951","DOI":"10.3390\/ijms24043951","article-title":"Lipidation of naturally occurring \u03b1-Helical antimicrobial peptides as a promising strategy for drug design","volume":"24","author":"Makowska","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"107821","DOI":"10.1016\/j.bioorg.2024.107821","article-title":"Impact of lipidation site on the activity of \u03b1-helical antimicrobial peptides","volume":"153","author":"Makowska","year":"2024","journal-title":"Bioorg. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jconrel.2018.12.032","article-title":"A review of lipidation in the development of advanced protein and peptide therapeutics","volume":"295","author":"Menacho-Melgar","year":"2019","journal-title":"J. Control. Release"},{"key":"B30","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1021\/acsinfecdis.1c00210","article-title":"Antimicrobial susceptibility testing of antimicrobial peptides requires new and standardized testing structures","volume":"7","author":"Meurer","year":"2021","journal-title":"ACS Infect. Dis."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1111\/febs.70298","article-title":"Artificial lipidation of proteins and peptides: from mechanism to clinical applications","volume":"293","author":"Mu","year":"2025","journal-title":"FEBS J."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2284685","DOI":"10.1080\/10717544.2023.2284685","article-title":"Lipidization as a tool toward peptide therapeutics","volume":"30","author":"My\u0161kov\u00e1","year":"2023","journal-title":"Drug Deliv."},{"key":"B33","doi-asserted-by":"publisher","first-page":"35329","DOI":"10.1039\/D0RA07679A","article-title":"Lipid membrane interactions of self-assembling antimicrobial nanofibers: effect of PEGylation","volume":"10","author":"Nielsen","year":"2020","journal-title":"RSC Adv."},{"key":"B34","doi-asserted-by":"publisher","first-page":"12531","DOI":"10.1038\/s41598-018-30282-3","article-title":"Reproducibility of antimicrobial test methods","volume":"8","author":"Parker","year":"2018","journal-title":"Sci. Rep."},{"key":"B35","doi-asserted-by":"publisher","first-page":"E8324","DOI":"10.1073\/pnas.1704489114","article-title":"Lipid topology and electrostatic interactions underpin lytic activity of linear cationic antimicrobial peptides in membranes","volume":"114","author":"Paterson","year":"2017","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1039\/C0MD00111B","article-title":"Strategies to prolong the plasma residence time of peptidedrugs","volume":"1","author":"Pollaro","year":"2010","journal-title":"Medchemcomm"},{"key":"B37","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1021\/acs.bioconjchem.4c00484","article-title":"Effect of lipidation on the structure, oligomerization, and aggregation of glucagon-like peptide 1","volume":"36","author":"P\u0159\u00e1da Brichtov\u00e1","year":"2025","journal-title":"Bioconjug. Chem."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2390","DOI":"10.1016\/j.chempr.2024.06.004","article-title":"Mirror-image protein and peptide drug discovery through mirror-image phage display","volume":"10","author":"Qi","year":"2024","journal-title":"Chem"},{"key":"B39","doi-asserted-by":"publisher","first-page":"701","DOI":"10.3390\/ijms17050701","article-title":"Design and application of antimicrobial peptide conjugates","volume":"17","author":"Reinhardt","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"3718","DOI":"10.1016\/j.bpj.2021.07.016","article-title":"Membrane hydrophobicity determines the activation free energy of passive lipid transport","volume":"120","author":"Rogers","year":"2021","journal-title":"Biophys. J."},{"key":"B41","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41570-025-00786-4","article-title":"Redefining peptide chemistry beyond accumulating analogues","volume":"10","author":"Roque-Borda","year":"2025","journal-title":"Nat. Rev. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"100104","DOI":"10.1016\/j.pharmr.2025.100104","article-title":"Synergistic combinations of antimicrobial peptides and conventional antibiotics: a strategy to delay resistance emergence in world health organization priority bacteria","volume":"78","author":"Roque-Borda","year":"2026","journal-title":"Pharmacol. Rev."},{"key":"B43","doi-asserted-by":"publisher","first-page":"9692","DOI":"10.3390\/ijms21249692","article-title":"Lipidation of antimicrobial peptides as a design strategy for future alternatives to antibiotics","volume":"21","author":"Rounds","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"014404","DOI":"10.1103\/PhysRevE.106.014404","article-title":"Free-energy landscapes and insertion pathways for peptides in membrane environment","volume":"106","author":"Sharma","year":"2022","journal-title":"Phys. Rev. E"},{"key":"B45","doi-asserted-by":"publisher","first-page":"11831","DOI":"10.1021\/acs.jmedchem.3c00406","article-title":"Structure\u2013activity relationships of the antimicrobial peptide natural product apidaecin","volume":"66","author":"Skowron","year":"2023","journal-title":"J. Med. Chem."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.3390\/antibiotics11111491","article-title":"Understanding the role of self-assembly and interaction with biological membranes of short cationic lipopeptides in the effective design of new antibiotics","volume":"11","author":"Stachurski","year":"2022","journal-title":"Antibiotics"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1016\/j.bbamem.2006.02.009","article-title":"Mode of action of the new antibiotic for Gram-positive pathogens daptomycin: Comparison with cationic antimicrobial peptides and lipopeptides","volume":"1758","author":"Straus","year":"2006","journal-title":"Biochimica Biophysica Acta (BBA) - Biomembr."},{"key":"B48","doi-asserted-by":"publisher","first-page":"xtag003","DOI":"10.1093\/femsmc\/xtag003","article-title":"Enhanced antibacterial activity of antimicrobial peptide\u2013antibiotic combinations against multidrug-resistant bacteria","volume":"7","author":"Talha","year":"2026","journal-title":"FEMS Microbes"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.3390\/pharmaceutics13111840","article-title":"Current advances in lipid and polymeric antimicrobial peptide delivery systems and coatings for the prevention and treatment of bacterial infections","volume":"13","author":"van Gent","year":"2021","journal-title":"Pharmaceutics"},{"key":"B50","doi-asserted-by":"publisher","first-page":"6797","DOI":"10.1039\/D1OB01227D","article-title":"New antimicrobial self-assembling short lipopeptides","volume":"19","author":"Vicente-Garc\u00eda","year":"2021","journal-title":"Org. Biomol. Chem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"183870","DOI":"10.1016\/j.bbamem.2022.183870","article-title":"Lipid tails modulate antimicrobial peptide membrane incorporation and activity","volume":"1864","author":"Walker","year":"2022","journal-title":"Biochimica Biophysica Acta (BBA) - Biomembr."},{"key":"B52","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.jconrel.2016.08.035","article-title":"The molecular basis for the prolonged blood circulation of lipidated incretin peptides: peptide oligomerization or binding to serum albumin?","volume":"241","author":"Wang","year":"2016","journal-title":"J. Control. Release"},{"key":"B53","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1038\/s41392-022-00904-4","article-title":"Therapeutic peptides: current applications and future directions","volume":"7","author":"Wang","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"B54","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1016\/j.molmet.2013.08.008","article-title":"Peptide lipidation stabilizes structure to enhance biological function","volume":"2","author":"Ward","year":"2013","journal-title":"Mol. Metab."},{"key":"B55","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/s41392-024-02107-5","article-title":"Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines","volume":"10","author":"Xiao","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.2174\/092986712799945003","article-title":"Converting peptides into drug leads by lipidation","volume":"19","author":"Zhang","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"B57","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1038\/s41392-024-01931-z","article-title":"Glucagon-like peptide-1 receptor: mechanisms and advances in therapy","volume":"9","author":"Zheng","year":"2024","journal-title":"Signal Transduct. Target. Ther."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2026.1807712\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T13:42:26Z","timestamp":1777902146000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2026.1807712\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,4]]},"references-count":57,"alternative-id":["10.3389\/fchem.2026.1807712"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2026.1807712","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,4]]},"article-number":"1807712"}}