Abstract
The pancreatic peptide hormone, amylin, plays a critical role in the control of appetite, and synergizes with other key metabolic hormones such as glucagon-like peptide 1 (GLP-1). There is opportunity to develop potent and long-acting analogues of amylin or hybrids between these and GLP-1 mimetics for treating obesity. To achieve this, interrogation of how the 37 amino acid amylin peptide engages with its complex receptor system is required. We synthesized an extensive library of peptides to profile the human amylin sequence, determining the role of its disulfide loop, amidated C-terminus and receptor "capture" and "activation" regions in receptor signaling. We profiled four signaling pathways with different ligands at multiple receptor subtypes, in addition to exploring selectivity determinants between related receptors. Distinct roles for peptide subregions in receptor binding and activation were identified, resulting in peptides with greater activity than the native sequence. Enhanced peptide activity was preserved in the brainstem, the major biological target for amylin. Interpretation of our data using full-length active receptor models supported by molecular dynamics, metadynamics, and supervised molecular dynamics simulations guided the synthesis of a potent dual agonist of GLP-1 and amylin receptors. The data offer new insights into the function of peptide amidation, how allostery drives peptide-receptor interactions, and provide a valuable resource for the development of novel amylin agonists for treating diabetes and obesity.
Original language | English |
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Pages (from-to) | 32-49 |
Number of pages | 18 |
Journal | ACS Pharmacology and Translational Science |
Volume | 1 |
Issue number | 1 |
Early online date | 23 Apr 2018 |
DOIs | |
Publication status | Published - 14 Sept 2018 |
Externally published | Yes |
Keywords
- amylin
- calcitonin receptor
- CGRP
- GPCR
- IAPP
- RAMP
ASJC Scopus subject areas
- Pharmacology (medical)
- Pharmacology
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Giuseppe Deganutti
- Centre for Health and Life Sciences - Assistant Professor (Research)
Person: Teaching and Research