| Autor: |
Sloop, Kyle W., Cox, Amy L., Wainscott, David B., White, Alex, Droz, Brian A., Stutsman, Cynthia, Showalter, Aaron D., Suter, Todd M., Dunbar, James D., Snider, Brandy M., O'Farrell, Libbey S., Hewitt, Natalie, Ruble, J. Craig, Padgett, Leah R., Woerly, Eric M., Peterson, Jeffrey A., Coskun, Tamer, Liu, Zhaomin, Coutant, David E., Ai, Minrong |
| Zdroj: |
Science Translational Medicine; 12/18/2024, Vol. 16 Issue 778, p1-15, 15p |
| Abstrakt: |
Orally bioavailable, synthetic nonpeptide agonists (NPAs) of the glucagon-like peptide-1 receptor (GLP-1R) may offer an effective, scalable pharmacotherapy to address the metabolic disease epidemic. One of the first molecules in the emerging class of GLP-1R NPAs is orforglipron, which is in clinical development for treating type 2 diabetes and obesity. Here, we characterized the pharmacological properties of orforglipron in comparison with peptide-based GLP-1R agonists and other NPAs. Competition binding experiments using either [125I]GLP-1(7-36)NH2 or [3H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant (Ki) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible β-arrestin recruitment. To evaluate GLP-1R engagement in vivo, mice expressing the human GLP-1R were administered orforglipron and subjected to a glucose tolerance test. Predicted receptor occupancy was calculated using the receptor Ki value of orforglipron and its unbound concentration in vivo that reduces hyperglycemia. These experiments revealed that low GLP-1R occupancy by orforglipron is sufficient to yield a full biological response. Moreover, in a model where CRISPR-Cas9 gene editing was used to sensitize the rat GLP-1R (Glp1rS33W) to GLP-1R NPAs, target engagement by orforglipron in the pancreas and brain was consistent with peptide-based GLP-1R agonists. Diet-induced obesity in Glp1rS33W rats enabled studies showing weight loss in animals orally administered orforglipron versus subcutaneous injection of GLP-1R agonist semaglutide. Furthermore, crossover studies indicated oral orforglipron can sustain efficacy initiated by parenteral semaglutide. The pharmacological properties of orforglipron may inform targeting of other peptide receptors with NPAs. Editor's summary: Nonpeptide, small-molecule agonists of the glucagon-like peptide-1 receptor (GLP-1R), offer attractive benefits over traditional peptide GLP-1R agonists, such as the potential for oral bioavailability. Sloop et al. examined the pharmacology of two such nonpeptide agonists currently in clinical trials for obesity and type 2 diabetes, orforglipron and danuglipron. The authors report ligand-binding characteristics at the human GLP-1R and downstream signaling events for each compound, comparing with common peptide GLP-1 analogs such as semaglutide. Glucose-lowering pharmacodynamics and weight loss were additionally assessed in rodent models. This study thus advances the pharmacology of GLP-1R nonpeptide agonists. —Catherine Charneski [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
