IDE-mediated GLP-1 degradation as the basis for designing long-acting and CNS-stable GLP-1 receptor agonists.

Authors

Lu Zhang, Xinyi Liu, Chenfang Si, Xianglong Hou, Xintian Hu, Yelin Chen, Junhao Hu, Christoph W Turck, Bing Shan, Yaoyang Zhang

Published in

Science advances. Volume 12. Issue 35. Pages eaeh4670. Aug 28, 2026. Epub Aug 26, 2026.

Abstract

Glucagon-like peptide-1 (GLP-1) is a key incretin hormone rapidly degraded by circulating proteases such as DPP-4. The metabolism of GLP-1 by other proteases, particularly tissue-resident proteases, remains largely unexplored. Here, we identify insulin-degrading enzyme (IDE) as a previously unknown GLP-1-degrading protease with two cleavage sites. We show that IDE-mediated degradation of GLP-1, but not insulin, represents a major mechanism regulating glucose control. To resist IDE, we engineered GLP-1 and Semaglutide with D-amino acid substitutions at these sites. These peptides exhibit enhanced stability in plasma, liver and intestinal secretomes, peritoneal fluid, and central nervous system (CNS). D-Ser¹⁸-Semaglutide shows prolonged plasma retention and sustained glucose-lowering effects in mice. Moreover, IDE knockdown and intracerebral injection of D-Ser¹⁸-Semaglutide confirm IDE's physiological role in GLP-1 degradation, particularly in the CNS. These findings reveal a previously unidentified regulatory mechanism of GLP-1 metabolism and provide a strategy for designing long-acting agonists with improved metabolic and CNS therapeutic potential.

PMID:
42647645
Bibliographic data and abstract were imported from PubMed on 27 Aug 2026.

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