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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\u2010term 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.<\/jats:p>","DOI":"10.1002\/cbic.202500237","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T22:10:13Z","timestamp":1751494213000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Adding A C\u2010Terminal Amino Acid Prevents the Conformational Interconversion of Plecantide Analogs"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8480-7631","authenticated-orcid":false,"given":"Yi","family":"Zhou","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering Guangxi University for Nationalities  Nanning 530006 China"},{"name":"Center for Innovative Drug Discovery Greater Bay Area Institute of Precision Medicine (Guangzhou)  Guangzhou 528441 P. 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