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Stabilized agonists of the GLP\u20101 receptor (GLP\u20101R) and dual agonists of GLP\u20101R and GIP receptor (GIPR) for the management of type\u20052 diabetes and obesity have generated widespread enthusiasm and have become blockbuster drugs. These therapeutics are refractory to the action of dipeptidyl peptidase\u20104 (DPP4), that catalyzes rapid removal of the two N\u2010terminal residues of the native peptides, in turn severely diminishing their activity profiles. Here we report that a\n                    <jats:italic>single<\/jats:italic>\n                    atom change from carbon to nitrogen in the backbone of the entire peptide makes them refractory to DPP4 action while still retaining full potency and efficacy at their respective receptors. This was accomplished by use of aza\u2010amino acids, that are bioisosteric replacements for \u03b1\u2010amino acids that perturb the structural backbone and local side chain conformations. Molecular dynamics simulations reveal that aza\u2010amino acid can populate the same conformational space that GLP\u20101 adopts when bound to the GLP\u20101R. The insertion of an aza\u2010amino acid at the second position from the N\u2010terminus in semaglutide and in a dual agonist of GLP\u20101R and GIPR further demonstrates its capability as a viable alternative to current DPP4 resistance strategies while offering additional structural variation that may influence downstream signaling.\n                  <\/jats:p>","DOI":"10.1002\/anie.202410237","type":"journal-article","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T14:21:47Z","timestamp":1723818107000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Potent and Protease Resistant Azapeptide Agonists of the GLP\u20101 and GIP Receptors"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7824-2121","authenticated-orcid":false,"given":"Tristan C.","family":"Dinsmore","sequence":"first","affiliation":[{"name":"Department of Chemistry Tufts University  02155 Medford 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