Master
English

The use of phage display technology to discover GLP-1R modulators

ContributorsBennani, Kenza
Number of pages56
Master program titleMaster II in Biomedical Sciences: Laboratory research internship
Defense date2025-01-28
Abstract

The prevalence of diabetes and obesity is on the rise and is expected to continue increasing in future generations. In response, innovative drugs for diabetes and obesity were developed, now accounting for the largest share in the market. One of the most important targets of these drugs is glucagon-like- peptide 1 receptor (GLP-1R), which has led to the development of several approved GLP-1R agonists (i.e. liraglutide, semaglutide, tirzepatide). These drugs are derived from the native GLP-1 peptide hormone, that activates GLP-1R and regulates blood glucose levels in the body. The N-terminal region of GLP-1 engages the transmembrane domain of GLP-1R to promote insulin secretion, delay gastric emptying and reduces appetite. Given the proven efficacy of GLP-1R-targeted therapies and the increasing interest about GLP- 1R, the aim of this project is to use the phage display technique developed in the Hartley Lab to identify GLP-1R peptide modulators. While this technology has been successfully used to identify promising therapeutic compounds, it has never been applied to GLP-1R. Capitalizing on the N-terminal region of GLP-1 being responsible for receptor activation, two phage libraries were constructed, with diversity inserted in the N-terminal region. The selection of libraries was performed on cells expressing GLP-1R. The recovered phage clones from the last round of selection were sequenced and synthesized using solid phase peptide synthesis (SPPS) (12 and 5 peptides respectively from library 1 and 2). Two independent cellular calcium flux assay experiments confirmed that all peptides are GLP-1R antagonists, with a wide range of potency. The most potent ones showing an IC50 ≤ 10 nM. The consistent antagonist potency across both experiments

Citation (ISO format)
BENNANI, Kenza. The use of phage display technology to discover GLP-1R modulators. Master, 2025.
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  • PID : unige:188378
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Creation05/08/2025 15:56:58
First validation20/10/2025 17:53:05
Update20/10/2025 17:53:05
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