{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:20:07Z","timestamp":1788495607237,"version":"build-2803163510"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Bioactive peptides derived from natural sources (marine organisms, plants, microbes, and fermented foods) exhibit potent antimicrobial, antihypertensive, antioxidant, and anticancer activities. However, their clinical translation is severely hindered by poor oral bioavailability, rapid proteolytic degradation, suboptimal pharmacokinetic profiles, and inconsistencies in sourcing and standardization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      This review critically examines experimental pharmacology strategies to overcome these translational barriers, including\n                      <jats:italic>in vitro<\/jats:italic>\n                      permeability models,\n                      <jats:italic>in vivo<\/jats:italic>\n                      pharmacokinetic profiling, chemical modifications (cyclization, D-amino acid substitution, N-methylation, PEGylation), advanced delivery systems (liposomes, polymeric nanoparticles, pH-responsive hydrogels), and emerging AI\/ML-guided approaches.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key findings<\/jats:title>\n                    <jats:p>\n                      Most unmodified natural peptides display apparent permeability coefficients below\n                      <jats:inline-formula>\n                        <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"m1\">\n                          <mml:mrow>\n                            <mml:mn>5<\/mml:mn>\n                            <mml:mo>\u00d7<\/mml:mo>\n                            <mml:msup>\n                              <mml:mn>10<\/mml:mn>\n                              <mml:mrow>\n                                <mml:mo>\u2212<\/mml:mo>\n                                <mml:mn>7<\/mml:mn>\n                              <\/mml:mrow>\n                            <\/mml:msup>\n                          <\/mml:mrow>\n                        <\/mml:math>\n                      <\/jats:inline-formula>\n                      cm\/s and plasma half-lives shorter than 15\u00a0min. Chemical modifications and nanocarrier systems demonstrably improve absorption and extend half-life, with reported increases in oral bioavailability of 3- to 10-fold in preclinical models. Success stories (ziconotide, lactotripeptides IPP\/VPP) versus stalled candidates highlight the decisive role of integrated experimental pharmacology data. Critical gaps remain, including limited human pharmacokinetic evidence, scalability of nanocarriers under GMP conditions, and harmonized regulatory pathways for natural-origin peptides.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Rigorous experimental pharmacology, rather than bioactivity alone, is the key to bridging the bench-to-bedside gap for natural bioactive peptides. A standardized translational workflow from discovery to IND filing is proposed to accelerate clinical application of these promising molecules.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1863016","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T10:29:33Z","timestamp":1786530573000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["From bench to bedside: experimental pharmacology approaches to overcome bioavailability, stability, and translational barriers of bioactive peptides from natural sources"],"prefix":"10.3389","volume":"17","author":[{"given":"Mamoudou","family":"Hamadou","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Biochemistry, Bioinformatics, and Bioactive Compounds for Health Promotion, Research Unit, Faculty of Science, University of Maroua","place":["Maroua, Cameroon"]},{"name":"Department of Chemistry, COMSATS University","place":["Islamabad, Pakistan"]},{"name":"Department Basic Science Education, National Advanced School of Engineering, University of Maroua","place":["Maroua, Cameroon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurav Kumar","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, University of North Bengal","place":["Darjeeling, West Bengal, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulhalim Musa","family":"Abubakar","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, Faculty of Engineering, Modibbo Adama University","place":["Yola, Adamawa, Nigeria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahri","family":"Ba\u015faran","sequence":"additional","affiliation":[{"name":"Department of Leather Engineering, Faculty of Engineering, Ege University","place":["Izmir, T\u00fcrkiye"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mune Mune","family":"Martin Alain","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Biochemistry, Bioinformatics, and Bioactive Compounds for Health Promotion, Research Unit, Faculty of Science, University of Maroua","place":["Maroua, Cameroon"]},{"name":"Faculty of Science, University of Yaound\u00e9 I","place":["Yaound\u00e9, Cameroon"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"105465","DOI":"10.1016\/j.ejps.2020.105465","article-title":"A molecular docking study repurposes FDA approved iron oxide nanoparticles to treat and control COVID-19 infection","volume":"153","author":"Abo-zeid","year":"2020","journal-title":"Eur. 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