Lithocholic Acid-Based Peptide Delivery System for an Enhanced Pharmacological and Pharmacokinetic Profile of Xenopus GLP-1 Analogs.

Abstract

GLP-1 analogs suffer from the main disadvantage of a short in vivo half-life. Lithocholic acid (LCA), one of the four main bile acids in the human body, possesses a high albumin binding rate. We therefore envisioned that a LCA-based peptide delivery system could extend the half-life of GLP-1 analogs by facilitating the noncovalent binding of peptides to human serum albumin. On the basis of our previously identified Xenopus GLP-1 analogs (1-3), a series of LCA-modified Xenopus GLP-1 conjugates were designed (4a-4r), and the bioactivity studies of these conjugates were performed to identify compounds with balanced in vitro receptor activation potency and plasma stability. 4c, 4i, and 4r were selected, and their LCA side chains were optimized to further increase their stability, affording 5a-5c. Compound 5b showed a more increased albumin affinity and prolonged in vitro stability than that of 4i and liraglutide. In db/ db mice, 5b exhibited comparable hypoglycemic and insulinotropic activity to liraglutide and semaglutide. Importantly, the enhanced albumin affinity of 5b resulted in a prolonged in vivo antidiabetic duration. Finally, chronic treatment investigations of 5b demonstrated the therapeutic effects of 5b on HbA1c, body weight, blood glucose, and pancreatic endocrine deficiencies on db/ db mice. Our studies revealed 5b as a promising antidiabetic candidate. Furthermore, our study suggests the derivatization of Xenopus GLP-1 analogs with LCA represents an effective strategy to develop potent long-acting GLP-1 receptor agonists for the treatment of type 2 diabetes.

• Authors: Jing Han, Xinyu Chen, Liming Zhao, Junjie Fu, Lidan Sun, Ying Zhang, Feng Zhou, Yingying Fei
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 15 Issue 7 Pg. 2840-2856 (07 02 2018) ISSN: 1543-8392 [Electronic] United States
• PMID: 29799205 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Xenopus Proteins
• semaglutide
• Lithocholic Acid
• Glucagon-Like Peptides
• Liraglutide
• Glucagon-Like Peptide 1
• Serum Albumin, Human

Topics

• Animals
• Blood Glucose (drug effects)
• Diabetes Mellitus, Experimental (blood, drug therapy)
• Diabetes Mellitus, Type 2 (blood, drug therapy)
• Drug Evaluation, Preclinical
• Drug Stability
• Glucagon-Like Peptide 1 (analogs & derivatives, chemistry, pharmacology)
• Glucagon-Like Peptides (pharmacology, therapeutic use)
• HEK293 Cells
• Half-Life
• Humans
• Hypoglycemic Agents (chemistry, pharmacology, therapeutic use)
• Liraglutide (pharmacology, therapeutic use)
• Lithocholic Acid (chemistry)
• Male
• Mice
• Mice, Inbred C57BL
• Rats
• Rats, Sprague-Dawley
• Serum Albumin, Human (metabolism)
• Treatment Outcome
• Xenopus Proteins (chemistry, pharmacology)