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Developing a novel exenatide-based incretin mimic (αB-Ex): Expression, purification and structural-functional
Mohammad Mehdi Ghanbarnezhad1, Mohammad Bagher Shahsavani1, Pramod S Mali2
1Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran.
Biochimica Et Biophysica Acta. General Subjects
|April 13, 2022
Summary
Researchers developed a novel hybrid protein, αB-Ex, by combining an exenatide analogue with human αB-crystallin. This new incretin mimic effectively reduces blood sugar and enhances insulin secretion, showing promise for type 2 diabetes mellitus treatment.
Area of Science:
- Biochemistry and Molecular Biology
- Pharmacology and Drug Discovery
- Endocrinology and Metabolism
Background:
- Glucagon-like peptide-1 (GLP-1) receptor agonists, such as exenatide, are established treatments for type 2 diabetes mellitus (T2DM) and obesity.
- There is an ongoing need for novel incretin mimics with improved pharmacokinetic profiles and therapeutic efficacy.
- Hybrid protein strategies offer a platform for developing new therapeutic agents with enhanced properties.
Purpose of the Study:
- To engineer and characterize a novel hybrid protein (αB-Ex) by conjugating an exenatide analogue to human αB-crystallin.
- To evaluate the biological activity of the exenatide analogue and the αB-Ex hybrid protein in vitro and in vivo.
- To assess the potential of αB-Ex as a therapeutic candidate for T2DM management.
Main Methods:
- Construction and bacterial expression of a fusion protein comprising an exenatide analogue and human αB-crystallin (αB-Ex).
- Purification of the exenatide analogue from the hybrid protein using gel filtration chromatography.
- Characterization using HPLC, ESI-MS, MALDI-TOF, DLS, and NMR; assessment of blood glucose-lowering and insulin-secreting effects in mice.
Main Results:
- High purity (>97%) and accurate molecular mass were confirmed for the exenatide analogue and the αB-Ex hybrid protein.
- Spectroscopic analyses indicated distinct secondary structures (α-helix for analogue, β-sheet for αB-Ex), with αB-Ex forming large oligomers.
- Both the exenatide analogue and αB-Ex demonstrated significant blood glucose reduction and insulin secretion induction in healthy and diabetic mice.
Conclusions:
- The study successfully developed and characterized a novel αB-Ex hybrid protein, a potential long-acting incretin mimic.
- αB-Ex exhibits potent glucose-lowering and insulin-stimulating activities, comparable to the exenatide analogue.
- The αB-Ex hybrid protein represents a promising drug candidate for the treatment of type 2 diabetes mellitus.
