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In addition to integrating the complementary actions of two endogenous metabolically related hormones targeting glucagon-like peptide-1 and glucagon receptors (GLP-1R and GCGR), the synergistic targeting of a third G protein-coupled receptor (GPCR), namely the gastric inhibitory polypeptide receptor (GIPR), may achieve optimal control of blood glucose levels and weight loss in patients with diabetes and obesity. In this work, we harness the predictive power of sequence-derived in silico mutagenesis to rationally design effective single-molecule peptides with triple-receptor-agonist activities. We model the binding profiles of our designed peptides to the GIP, GLP-1 and GCG receptor triad through multiple, long, repeat molecular simulations and effective binding enthalpy calculations to assess their predicted multi-receptor engagement profiles. Our data predict a balanced, highly favourable effective binding enthalpy profile of our newly designed peptides for the three receptors compared to endogenous peptides and the experimental reference peptides, with high targeted specificity for the receptors. The peptides are further engineered to structurally support metabolic stability by substituting sites prone to proteolytic cleavage. The predicted triple-hormone-receptor agonist peptide mechanism opens new avenues for the synthesis and activity testing of multi-targeting peptides with improved stability, offering a computational design strategy for testing the potential reduction of adverse gastrointestinal effects of peptide therapeutics and support future development of lower-dose oral formulations.<\/jats:p>","DOI":"10.1007\/s10822-026-00903-5","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T04:31:43Z","timestamp":1785385903000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design of a metabolically-stable peptide therapeutic with triple-hormone-receptor agonist activity"],"prefix":"10.1007","volume":"40","author":[{"given":"Shubham","family":"Vishnoi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Hudson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shayon","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"issue":"11","key":"903_CR1","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1038\/nrg2468","volume":"9","author":"AJ Lusis","year":"2008","unstructured":"Lusis AJ, Attie AD, Reue K (2008) Nat Rev Genet 9(11):819","journal-title":"Nat Rev Genet"},{"issue":"1","key":"903_CR2","doi-asserted-by":"publisher","first-page":"3987","DOI":"10.1038\/s41598-024-54367-4","volume":"14","author":"Z Jamali","year":"2024","unstructured":"Jamali Z, Ayoobi F, Jalali Z, Bidaki R, Lotfi MA, Esmaeili-Nadimi A, Khalili P (2024) Sci Rep 14(1):3987","journal-title":"Sci Rep"},{"issue":"1","key":"903_CR3","doi-asserted-by":"publisher","first-page":"15019","DOI":"10.1038\/nrdp.2015.19","volume":"1","author":"RA DeFronzo","year":"2015","unstructured":"DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, Hu FB, Kahn CR, Raz I, Shulman GI, Simonson DC, Testa MA, Weiss R (2015) Nat Rev Dis Primers 1(1):15019","journal-title":"Nat Rev Dis Primers"},{"issue":"2","key":"903_CR4","first-page":"142","volume":"38","author":"AS Barnes","year":"2011","unstructured":"Barnes AS (2011) Tex Heart Inst J 38(2):142","journal-title":"Tex Heart Inst J"},{"issue":"10431","key":"903_CR5","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1016\/S0140-6736(23)02750-2","volume":"403","author":"NH Phelps","year":"2024","unstructured":"Phelps NH, Singleton RK, Zhou B, Heap RA, Ezzati M (2024) The Lancet 403(10431):1027","journal-title":"The Lancet"},{"issue":"3","key":"903_CR6","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/nrd.2015.4","volume":"15","author":"DY Oh","year":"2016","unstructured":"Oh DY, Olefsky JM (2016) Nat Rev Drug Discovery 15(3):161","journal-title":"Nat Rev Drug Discovery"},{"issue":"S3","key":"903_CR7","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1111\/dom.14496","volume":"23","author":"MA Nauck","year":"2021","unstructured":"Nauck MA, Quast DR, Wefers J, Pfeiffer AFH (2021) Diabetes Obes Metab 23(S3):5","journal-title":"Diabetes Obes Metab"},{"issue":"3","key":"903_CR8","doi-asserted-by":"publisher","first-page":"R65","DOI":"10.1530\/JOE-20-0119","volume":"246","author":"B Khoo","year":"2020","unstructured":"Khoo B, Tan TM-M (2020) J Endocrinol 246(3):R65","journal-title":"J Endocrinol"},{"issue":"4","key":"903_CR9","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1152\/physrev.00034.2006","volume":"87","author":"JJ Holst","year":"2007","unstructured":"Holst JJ (2007) Physiol Rev 87(4):1409","journal-title":"Physiol Rev"},{"key":"903_CR10","doi-asserted-by":"crossref","unstructured":"Chandarana R, D\u2019Souza JS, Coutinho EC (2012) Glucose-dependent insulinotropic polypeptide receptor (GIPR). 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