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Engineering an enhanced thrombin-based GLP-1 analog with long-lasting glucose-lowering and efficient weight reduction
Hongchao Pan1, Yini Xie2, Wenying Lu3
1Department of Laboratory Medicine, Shanghai Simple Gene Medical Laboratory Shanghai 200025 P.R. China.
RSC Advances
|May 9, 2022
Summary
Researchers developed novel long-acting glucagon-like peptide-1 (GLP-1) analogs (XTS1 and XTS2) by incorporating an albumin-binding domain. XTS1 demonstrated superior albumin binding, metabolic stability, and prolonged glucose-lowering effects, showing potential for type 2 diabetes treatment.
Area of Science:
- Biochemistry and Pharmacology
- Drug Discovery and Development
Background:
- Peptide drugs offer high potency and selectivity but suffer from poor in vivo stability, limiting their clinical use.
- Developing strategies to prolong peptide drug half-life is crucial for effective therapeutic applications.
Purpose of the Study:
- To design and evaluate novel, long-acting glucagon-like peptide-1 (GLP-1) analogs with enhanced in vivo half-lives.
- To assess the therapeutic potential of these analogs for managing type 2 diabetes mellitus (T2DM).
Main Methods:
- Design of two GLP-1 analogs (XTS1, XTS2) featuring an albumin-binding domain and a protease-cleavable linker.
- Characterization using reversed-phase high-performance liquid chromatography and mass spectrometry.
- In vitro assessment of albumin binding affinity (surface plasmon resonance), metabolic stability, and protease cleavage.
- In vivo evaluation in rodent and non-human primate models, including glucose tolerance tests and pharmacokinetic studies.
- Long-term efficacy assessment in db/db mice for body weight, HbA1c, and pancreatic beta-cell function.
Main Results:
- XTS1 exhibited higher affinity for serum albumins and superior in vitro metabolic stability compared to XTS2.
- Controlled release of active GLP-1 was confirmed via thrombin-catalyzed hydrolysis.
- XTS1 demonstrated dose-dependent glucose-lowering effects, with superior duration and efficacy compared to Liraglutide in vivo.
- Extended plasma half-lives of approximately 2.3 and 3.5 days were observed in rats and cynomolgus monkeys, respectively.
- XTS1 treatment in db/db mice led to sustained improvements in body weight, HbA1c levels, and pancreatic beta-cell function.
Conclusions:
- The designed albumin-binding polypeptide strategy effectively prolongs the duration of action for GLP-1 analogs.
- XTS1 demonstrates significant potential as a long-acting therapeutic agent for type 2 diabetes.
- Further clinical investigation of XTS1 for T2DM treatment is warranted.
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