Exendin-4 and Its Related Peptides

Michelle Khai Khun Yap, Nurhamimah Misuan

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Researchpeer-review


Exendin-4 is a 39-residue incretin-mimetic peptide from the venom of Heloderma suspectum (Gila monster) and H. horridum (beaded lizard). It is a venom analog of mammalian glucagon-like peptide-1 (GLP-1) and a full agonist towards the GLP-1 receptor to produce insulinotropic effects. The structural properties of exendin-4 explain its better agonistic effect on the GLP-1 receptor as compared with the endogenous GLP-1 peptide. The helical region of the peptide interacts with the extracellular N-terminal domain (NTD) of the GLP-1 receptor, while the C-terminal Trp cage further intensifies its binding to the receptor. Exendin-4 may act as an allosteric modulator to enable in-depth interaction of NTD with the core domain of the GLP-1 receptor, leading to receptor activation. Its promising agonistic effects on the GLP-1 receptor help to preserve normal physiological functions of pancreatic β-cells through anti-apoptotic, antioxidative and anti-inflammatory actions. Moreover, exendin-4 can also attenuate diabetic-related complications such as neuropathy, nephropathy and ventricular remodeling via activation of the GLP-1 receptor. Exendin-4 is more resistant to hydrolysis by dipeptidyl-peptidase 4 and thus, exhibits a longer biological half-life than GLP-1. Therefore, it presents as a preferred therapeutic option for diabetes compared with GLP-1. Furthermore, the neuroprotective properties of exendin-4 have highlighted its potential in the treatment of neurodegenerative diseases, for example, Alzheimer’s disease and Parkinson’s disease. Although exendin-4 has a reasonable subcutaneous bioavailability, its biological half-life is only up to 4 hours, and a repeated dosing regimen is required to maintain its therapeutic levels. Future efforts should be directed toward a different modification approach to improve the pharmacological properties of existing exendin-4. This chapter focuses on an overview of exendin-4 and its related peptides, their pharmacological properties, and their structure–activity relationships with the GLP-1 receptor.
Original languageEnglish
Title of host publicationHandbook of Venoms and Toxins of Reptiles
EditorsStephen P. Mackessy
Place of PublicationBoca Raton FL USA
PublisherCRC Press
Number of pages19
ISBN (Electronic)9780429054204
ISBN (Print)9780367149741, 9780367769468
Publication statusPublished - 2021

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