Small-molecule albumin ligand modification to enhance the anti-diabetic ability of GLP-1 derivatives

Xiaoliang Sun; Ziyuan Zhang; Meiyan Liu; Peng Zhang; Liqin Nie; Yuqing Liu; Ye Chen; Fengjiao Xu; Zhonghua Liu; Youlin Zeng

doi:10.1016/j.biopha.2022.112722

Small-molecule albumin ligand modification to enhance the anti-diabetic ability of GLP-1 derivatives

Biomed Pharmacother. 2022 Apr:148:112722. doi: 10.1016/j.biopha.2022.112722. Epub 2022 Feb 21.

Authors

Xiaoliang Sun¹, Ziyuan Zhang², Meiyan Liu¹, Peng Zhang³, Liqin Nie¹, Yuqing Liu¹, Ye Chen¹, Fengjiao Xu¹, Zhonghua Liu³, Youlin Zeng⁴

Affiliations

¹ Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education of China, Hunan Normal University, Changsha 410081, China; Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, Hunan Normal University, Changsha 410081, China.
² Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education of China, Hunan Normal University, Changsha 410081, China.
³ The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha Hunan 410081, China.
⁴ Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education of China, Hunan Normal University, Changsha 410081, China; Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, Hunan Normal University, Changsha 410081, China. Electronic address: youlinzengcn@hunnu.edu.cn.

PMID: 35202915
DOI: 10.1016/j.biopha.2022.112722

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists modified with albumin ligands which can specificity bind to the human serum albumin (HSA) was an efficient strategy to prolong the half-time of GLP-1. Herein, we investigated the effect of small-molecule albumin ligand modification on the hypoglycemic activities of GLP-1 derivatives. Two GLP-1 derivatives MPA-C12-GLP-1 and Rhein-C12-GLP-1 were achieved by modification of the side chain amino of lysine in position 26 of the Arg34-GLP-1(7-37)-OH with Rhein and 3-Maleimidopropionic acid respectively using 12-aminolauric acid as a linker, and its specific albumin-conjugating characteristics, pharmaceutical characterization, and the antidiabetic effects were investigated. In vitro level, two GLP-1 derivatives demonstrated a higher binding capacity to GLP-1 receptor than that of Arg34-GLP-1(7-37)-OH. Interestingly, although the binding ability of MPA-C12-GLP-1 was equal to liraglutide, the binding ability of Rhein-C12-GLP-1 was 10-fold higher than liraglutide. In vivo level, the two GLP-1 derivatives can significantly increase their glucose tolerance and prolong their half-life in ICR mice, and they were also superior to GLP-1 in controlling glucose homeostasis and suppression of food intake and water consumption in db/db mice. Importantly, the two GLP-1 derivatives showed comparable efficacy to liraglutide for the therapy of type 2 diabetes mellitus. The in vitro INS-1 cells toxicity and the in vivo hepatotoxicity indicated that the Rhein-C12-GLP-1 was a safe candidate for the therapy of type 2 diabetes, and the serum biomarkers determination results showed that the Rhein-modified GLP-1 could significantly improve the HbA_1c and blood lipids, and the H&E stain exhibited that the Rhein-C12-GLP-1 can effectively promote β-cell proliferation and differentiation. In conclusion, the 3-Maleimidopropionic acid or Rhein-modified GLP-1derivatives have great potential for development as a Type 2 diabetes mellitus therapeutic drug.

Keywords: Anti-diabetic ability; Glucagon like peptide-1 (GLP-1); Mellitus; Small-Molecule Albumin Ligand; Type 2 diabetes.

MeSH terms

Albumins / therapeutic use
Animals
Blood Glucose
Diabetes Mellitus, Type 2* / drug therapy
Glucagon-Like Peptide 1* / metabolism
Hypoglycemic Agents / chemistry
Ligands
Mice
Mice, Inbred C57BL
Mice, Inbred ICR

Substances

Albumins
Blood Glucose
Hypoglycemic Agents
Ligands
Glucagon-Like Peptide 1