Summer is coming soon, are you ready for your body?
Obesity has become a global epidemic, and the incidence of obesity continues to soar in countries around the world. According to the World Health Organization (WHO), 13% of adults worldwide suffer from obesity. More than 507 million people suffer from type 2 diabetes and 890 million suffer from obesity. Glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon receptor (GCGR) are important "regulators" for maintaining blood sugar balance in the human body. More importantly, obesity can further cause metabolic syndrome and various complications, such as type 2 diabetes, hypertension, non-alcoholic steatohepatitis (NASH), cardiovascular disease and cancer.
In June 2021, the FDA approved the listing of Semaglutide, a weight loss drug developed by Novo Nordisk, under the trade name Wegovy. Due to its excellent weight loss effect, good safety, and the promotion of celebrities such as Musk, Semaglutide has become popular all over the world, and even a drug has become hard to find. According to the 2022 annual report released by Novo Nordisk, semaglutide's sales in 2022 will reach $12 billion.
GLP-1R promotes insulin release, inhibits glucagon secretion, reduces appetite, and lowers blood sugar and body weight; GIPR increases insulin secretion when blood sugar rises, stimulates glucagon release when blood sugar is low, and plays a role in lipid metabolism; GCGR regulates liver sugar, lipid and protein metabolism. The most effective treatments currently include GLP-1R agonists such as semaglutide and the GLP-1R/GIPR dual agonist tirzepatide. These drugs work by activating key receptors that regulate blood sugar homeostasis, but these drugs do not target GCGR.
2. Research focus
Recently, a drug called Retatrutide (also known as LY3437943, Retatrutide) has shown significant effects in the treatment of obesity by triple activation of GLP-1R, GIPR and GCGR (Figure 1). Compared with the corresponding endogenous peptide, Retatrutide is 8.9 times more potent on GIPR, and 0.3 and 0.4 times less potent on GCGR and GLP1R, respectively. Retatrutide has shown great potential in the treatment of obesity and metabolic diseases. Its unique molecular structure not only improves drug stability and bioavailability, but also significantly prolongs its half-life, making it perform well in clinical applications. With further research and promotion, Retatrutide is expected to become a blockbuster drug in the next few years, bringing good news to millions of patients around the world.
3. Research results
3.1. Retatrutide induced stronger weight loss in obese mice than Tirzepatide, which was achieved by activating GCGR and thus increasing energy expenditure.
3.2. In a phase II clinical trial of type 2 diabetes, Retatrutide reduced weight by an average of 17.5% in 24 weeks and 24.2% in 48 weeks in the 12 mg dose group. Retatrutide showed improved blood sugar control and significant weight loss, and its safety was comparable to that of some approved GLP1RAs.
4. Structural analysis
The structures of GLP-1R, GIPR and GCGR bound to Retatrutide were determined using cryo-electron microscopy (cryo-EM) technology (Figure 2). These structures reveal how Retatrutide achieves triple agonist effects by maintaining common interactions with conserved residues and different interactions with different receptor-specific residues.
From a sequence perspective, Retatrutide (Figure 3) is a single peptide composed of 39 amino acids, designed based on the GIP peptide backbone, and is able to achieve triple agonist activity on GCGR, GIPR and GLP-1R. Its peptide backbone sequence contains three non-coding amino acid residues at positions 2, 20 and 13: Aib2 (α-aminoisobutyric acid) provides stability against hydrolysis by DPP4 (a peptide hydrolase), Aib20 optimizes GIP activity and pharmacokinetics (PK), and AMeL13 (α-methyl-L-leucine) improves the activity of GCG and GIP. The backbone is coupled to the C20 fatty acid dicarboxylic acid moiety via a linker at the 17th lysine residue, allowing it to bind to plasma albumin (human serum albumin), prolonging the pharmacokinetic half-life while providing the desired pharmacological properties.
5. Conclusion
The study provides valuable insights into Retatrutide as a single molecule triple agonist that simultaneously activates GLP-1R, GIPR, and GCGR. These structures, compared with the binding modes of other dual and triple agonists, highlight the selectivity of the receptors conferred by the N-terminal and C-terminal regions of the peptide, while the middle region provides opportunities for sequence optimization to improve the balance between different receptor activation activities, thus providing a useful template for designing better single molecule therapeutic drugs.
Retatrutide powder is an experimental drug developed by Eli Lilly for the treatment of obesity. It is a triple chelator receptor agonist for GLP-1, GlP and GCGR receptors. In Phase 1 clinical trials, the drug has been shown to reduce average weight by more than 24% in non-diabetic but obese or pre-obese (overweight) adults. Retatrutide (Y'3437943) is an agonist of glucose-dependent insulin secretagogue polypeptide, glucagon-like peptide 1 and glucagon receptors. The United States recently approved Eli Lilly's Zepbound for the treatment of obesity in adults. The drug is also sold under the trade name Mounjaro for the treatment of type 2 diabetes in adults. Studies have shown that it can also improve liver health by reducing liver fat.
Therefore, although the weight loss magic drug can significantly reduce weight, it is also necessary to master the indications when it is used clinically, especially for people who are not obese, and should be used with caution!