Bicyclic Peptide Conformational Locks: Plecanatide, an FDA-endorsed therapy for chronic idiopathic constipation and irritable bowel syndrome with constipation, faces stability challenges in acidic environments. The innovative approach involved appending a functional amino acid to the C-termini, transforming plecanatide into highly stable isomers that retained or enhanced their GC-C agonistic activity.

The principle of structure dictating properties is illustrated by the direct correlation between cyclic peptide conformation and their biological efficacy. Plecanatide, a synthetic analog of uroguanylin, has received FDA approval for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. Nevertheless, our investigation has revealed that plecanatide undergoes slow conformational interconversion in slightly acidic conditions. In response, propargylglycine is strategically incorporated at the carboxyl terminal of plecanatide, a modification that not only facilitates additional functionalization and derivatizationbut also confers exceptional conformational stability. Remarkably, the resulting isomers not only maintained long-term conformational stability but also exhibited either preserved or slightly enhanced agonistic activity. This discovery represents a contribution to drug research focused on plecanatide, particularly in elucidating the relationship between its conformational properties and biological activity.