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Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion
Published on: May 10, 2018
DPP-IV-resistant, long-acting oxyntomodulin derivatives.
Alessia Santoprete1, Elena Capitò, Paul E Carrington
1Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy.
Summary
Oxyntomodulin analogs show promise for treating obesity and type 2 diabetes by improving glucose control and promoting weight loss. Modifications enhance their stability and potency, offering a potential therapeutic advantage.
Area of Science:
- Endocrinology and Metabolic Diseases
- Pharmacology and Drug Discovery
Background:
- Obesity is a major risk factor for type 2 diabetes, necessitating treatments for both glucose control and weight loss.
- Glucagon-like peptide 1 (GLP-1) mimetics offer glucose-dependent insulin secretion and weight loss but can cause nausea.
- Oxyntomodulin (OXM), a dual GLP-1 and glucagon receptor agonist, reduces food intake and body weight with fewer side effects than GLP-1 mimetics.
Purpose of the Study:
- To develop novel oxyntomodulin (OXM) analogs with improved pharmacokinetic and pharmacodynamic properties for potential therapeutic use.
- To investigate the impact of structural modifications on OXM's stability against dipeptidyl peptidase IV (DPP-IV) degradation and receptor activity.
Main Methods:
- Structure-activity relationship (SAR) studies were conducted on oxyntomodulin (OXM).
- Analogs were synthesized and modified, including derivatization with a cholesterol moiety.
- Resistance to DPP-IV degradation, in vivo duration of action, and receptor selectivity (GLP-1R vs. GCGR) were assessed.
Main Results:
- Novel OXM analogs resistant to DPP-IV degradation were identified, exhibiting increased potency compared to native OXM.
- Cholesterol-derivatized analogs demonstrated an extended duration of action in vivo.
- A single amino acid substitution was found to convert the dual GLP-1R/GCGR agonist into a selective GLP-1R agonist.
Conclusions:
- Modified OXM analogs offer enhanced stability and potency, addressing the limitations of short circulatory half-life.
- Dual GLP-1R/GCGR agonists represent a promising therapeutic class for obesity and type 2 diabetes, potentially superior to selective GLP-1R agonists.
- The ability to modulate receptor selectivity provides a versatile platform for developing targeted metabolic therapies.
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