Kyle W. Sloop, Amy L. Cox, David B. Wainscott, Alex White, Brian A. Droz, Cynthia Stutsman, Aaron D. Showalter, Todd M. Suter, James D. Dunbar, Brandy M. Snider, Libbey S. O’Farrell, Natalie Hewitt, J. Craig Ruble, Leah R. Padgett, Eric M. Woerly, Jeffrey A. Peterson, Tamer Coskun, Zhaomin Liu, David E. Coutant, Minrong Ai, Paul J. Emmerson, Panjamaporn Sangwung, Francis S. Willard
{"title":"奥锻利戎对 GLP-1 受体的非肽激动作用的药理学基础","authors":"Kyle W. Sloop, Amy L. Cox, David B. Wainscott, Alex White, Brian A. Droz, Cynthia Stutsman, Aaron D. Showalter, Todd M. Suter, James D. Dunbar, Brandy M. Snider, Libbey S. O’Farrell, Natalie Hewitt, J. Craig Ruble, Leah R. Padgett, Eric M. Woerly, Jeffrey A. Peterson, Tamer Coskun, Zhaomin Liu, David E. Coutant, Minrong Ai, Paul J. Emmerson, Panjamaporn Sangwung, Francis S. Willard","doi":"10.1126/scitranslmed.adp5765","DOIUrl":null,"url":null,"abstract":"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 [ <jats:sup>125</jats:sup> I]GLP-1(7-36)NH <jats:sub>2</jats:sub> or [ <jats:sup>3</jats:sup> H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant ( <jats:italic>K</jats:italic> <jats:sub>i</jats:sub> ) = 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 <jats:italic>K</jats:italic> <jats:sub>i</jats:sub> 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 ( <jats:italic> Glp1r <jats:sup>S33W</jats:sup> </jats:italic> ) 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 <jats:italic> Glp1r <jats:sup>S33W</jats:sup> </jats:italic> 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.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"19 1","pages":""},"PeriodicalIF":15.8000,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron\",\"authors\":\"Kyle W. Sloop, Amy L. Cox, David B. Wainscott, Alex White, Brian A. Droz, Cynthia Stutsman, Aaron D. Showalter, Todd M. Suter, James D. Dunbar, Brandy M. Snider, Libbey S. O’Farrell, Natalie Hewitt, J. Craig Ruble, Leah R. Padgett, Eric M. Woerly, Jeffrey A. Peterson, Tamer Coskun, Zhaomin Liu, David E. Coutant, Minrong Ai, Paul J. Emmerson, Panjamaporn Sangwung, Francis S. Willard\",\"doi\":\"10.1126/scitranslmed.adp5765\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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 [ <jats:sup>125</jats:sup> I]GLP-1(7-36)NH <jats:sub>2</jats:sub> or [ <jats:sup>3</jats:sup> H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant ( <jats:italic>K</jats:italic> <jats:sub>i</jats:sub> ) = 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 <jats:italic>K</jats:italic> <jats:sub>i</jats:sub> 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 ( <jats:italic> Glp1r <jats:sup>S33W</jats:sup> </jats:italic> ) 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 <jats:italic> Glp1r <jats:sup>S33W</jats:sup> </jats:italic> 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. 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The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron
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 [ 125 I]GLP-1(7-36)NH 2 or [ 3 H]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 ( Glp1r S33W ) 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 Glp1r S33W 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.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
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