GLP-1 and Obesity Research

Liraglutide is the first approved GLP-1RA for obesity treatment, which is designed based on native GLP-1(7–37).

Liraglutide was engineered by conjugating a C16 saturated fatty acid (palmitic acid) to the side chain of Lys26 in GLP-1(7–37), thereby enhancing albumin binding. In addition, Lys34 was substituted with Arg to prevent nonspecific acylation at multiple Lys residues. These modifications prolong its plasma half-life to approximately 13 hours ^[7].

Semaglutide has emerged as a landmark GLP-1RA, owing to its unprecedented weight-loss efficacy and remarkable commercial success in the anti-obesity drug market.

Semaglutide is also a long-acting GLP-1RA engineered from native GLP-1(7–37). Through multiple structural modifications, it markedly improves in vivo stability and prolongs its half-life while largely retaining high affinity for the GLP-1R.

In semaglutide, a C18 fatty diacid moiety is conjugated to the side chain of Lys26 via a hydrophilic linker, enabling reversible binding to plasma albumin and prolonged systemic exposure. In addition, Lys34 is substituted with Arg to prevent nonspecific acylation. And Ala8 is replaced with a non-natural amino acid Aib (α-aminoisobutyric acid), thereby markedly enhancing resistance to DPP-4-mediated degradation and extending the plasma half-life to approximately 7 days ^[7].

Orforglipron (LY3502970) is a non-peptide, small molecule oral GLP-1RA developed for weight management and T2D. Specifically, orforglipron is designed as a potent partial agonist of the GLP-1R that has a greater effect on cyclic AMP (cAMP) signaling than on β-arrestin recruitment. This biased agonism may offer lower receptor desensitization than full GLP-1 receptor agonists. Orforglipron has a half-life of 29-49 hours, supporting once-daily administration. Clinical trials indicate mild to moderate adverse events which were mostly gastrointestinal effects ^[8].

Tirzepatide is a dual GLP‑1R/GIPR agonist engineered based on incretins. It demonstrates superior efficacy over single‑target GLP‑1 RAs in glycemic and body weight management, and can be applied in T2D and obesity researches.

Tirzepatide is a 39-mer peptide engineered from GLP-1, GIP, and exenatide segments. Substitution with Aib at positions 2 and 13 results in DPP-4 resistance and increased stability. A C20 fatty di-acid moiety is added at Lys-20 for albumin binding, extending the half-life to five days (Figure 6) ^[9].

Figure 7. Structure of retatrutide ^[10]

Retatrutide is a leading multi-receptor agonist candidate in phase III clinical development, activating GLP-1R, GIPR, and GCGR. By integrating multiple metabolic regulatory signals into a single peptide scaffold, retatrutide enables synergistic regulation of glucose homeostasis, body weight, and energy metabolism.

 

Structurally, retatrutide is based on a GIP/GLP-1 peptide scaffold incorporating key glucagon-derived residues, thereby conferring triple receptor agonism. Similar to semaglutide, retatrutide also incorporates Aib substitution and fatty acid conjugation to enhance metabolic stability and prolong its plasma half-life ^[10].

Amycretin is a rationally designed unimolecular dual receptor agonist derived from the amylin and GLP-1 scaffolds. By simultaneously activating GLP-1R and AMYR, it enables synergistic regulation of energy homeostasis and body weight, demonstrating remarkable weight-loss efficacy in clinical trials.

Amycretin consists of 68 amino acids and is formed by linking the GLP-1R agonist moiety and the AMYR agonist moiety via a linker peptide (GGGGE). The GLP-1R agonist moiety incorporates the unnatural amino acid Aib and long-chain fatty acid modifications to enhance stability and elongate the half-life (Figure 8) ^[11].