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.

Stapled, Long-Acting Xenopus GLP-1-Based Dual GLP-1/Glucagon Receptor Agonists with Potent Therapeutic Efficacy for Metabolic Disease

“…24 In addition, in our previous research, lithocholic acid with a C12 alkyl chain has been successfully applied to xGLP-1 as an alternative means for the development of long-acting GLP-1R agonists, and thus, lithocholic acid with a C12 alkyl chain was also used as an albumin binder and introduced to the SYM-BisMAL. 16 However, the introduction of a fatty acid or lithocholic acid as an albumin binder might lead to potency loss of peptides due to steric interference with receptor recognition, as well as the lipophilicity of lithocholic acid and fatty acids. We predicted that a short spacer between the fatty acid or lithocholic acid and peptide backbone could help to alleviate the abovementioned negative impacts, as well as providing more opportunities for structural tuning.…”

“…Moreover, our previous studies conducted on xGLP-1 revealed that long-acting xGLP-1 derivatives have many beneficial antidiabetic effects, including slowing of gastric emptying, weight loss due to reduced food intake, glucose-dependent promotion of insulin secretion, and increase in β-cell mass/area and pancreas function. 15,16 Many of the dual GLP-1R/GCGR agonists described previously are based on the structures of OXM, glucagon, or exendin-4, leading to a big challenge to tune and optimize the physicochemical properties. 17 Due to its favorable physicochemical properties, xGLP-1 was an attractive scaffold for the development of novel dual GLP-1R and GCGR agonists.…”

Elucidation of The Effects and Underlying Mechanism of Aerobic Interval Training Combined With Liraglutide On Diabetic Cardiomyopathy

“…Liraglutide is produced by the non-covalent binding of GLP-1 and albumin [36]. The half-life of liraglutide is relatively long, up to 13 hours [37]. In the diabetic patients who were administered liraglutide, the left ventricular mass index was signi cantly lesser than that in the control group, and the left ventricular endsystolic volume and left ventricular end-diastolic volume were lower, suggesting that liraglutide prevents left ventricular remodeling in diabetic patients [38].…”

Recent Progress in Macromolecular Design and Synthesis of Bile Acid‐Based Polymeric Architectures

“…Han et al have designed and synthesized LCA-based polypeptide module through fluorenylmethyloxycarbonyl (Fmoc) directed peptide synthetic strategy. [86] This synthetic method revealed the coupling of LCA after removal of Fmoc protection at the amine site of the peptide. Subsequent removal of all side chain protecting groups through resin cleavage resulted in the formation of final LCA conjugated peptide material.…”