pH Controlled transient cyclization of peptides for increased stability towards oral delivery

Peptides are highly efficient for treatment of many diseases, especially in oncology and diabetes. Oral delivery of peptides is desirable, but is challenged by low bioavailability and new chemical methods to enable oral delivery are needed. Here, we developed pH responsive linearization as a strategy for transient protection of peptides to extend their half‐life in model systems. Peptides were cyclized to increase their stability at the low pH in the stomach, while they linearize at neutral pH to form the active peptide. We developed ester based responsive linkers with a protonable amine for O‐to‐N acyl shift, which allowed linearization strategies based on pyroglutamoyl (pGlu) or diketopiperazine (DKP) formation. After coupling of the linker, peptides were cyclized by CuAAC. We studied the stability against simulated gastric fluid (SGF) at different pH and the ability of cyclic peptides to linearize. This led to PYY3‐36 analogues with pH responsive linearization for increased stability.