{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:28:22Z","timestamp":1791998902305,"version":"4.4.0"},"reference-count":45,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"778","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,12,18]]},"abstract":"<jats:p>\n            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 [\n            <jats:sup>125<\/jats:sup>\n            I]GLP-1(7-36)NH\n            <jats:sub>2<\/jats:sub>\n            or [\n            <jats:sup>3<\/jats:sup>\n            H]orforglipron indicated that orforglipron is a high-affinity [inhibition constant (\n            <jats:italic>K<\/jats:italic>\n            <jats:sub>i<\/jats:sub>\n            ) = 1 nM], selective ligand of the human GLP-1R. Signal transduction assays showed that orforglipron has low intrinsic efficacy for effector activation and negligible \u03b2-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\n            <jats:italic>K<\/jats:italic>\n            <jats:sub>i<\/jats:sub>\n            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 (\n            <jats:italic>\n              Glp1r\n              <jats:sup>S33W<\/jats:sup>\n            <\/jats:italic>\n            ) 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\n            <jats:italic>\n              Glp1r\n              <jats:sup>S33W<\/jats:sup>\n            <\/jats:italic>\n            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.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adp5765","type":"journal-article","created":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T19:00:17Z","timestamp":1734548417000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":54,"title":["The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6748-9929","authenticated-orcid":true,"given":"Kyle W.","family":"Sloop","sequence":"first","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1571-6016","authenticated-orcid":true,"given":"Amy L.","family":"Cox","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8790-1703","authenticated-orcid":true,"given":"David B.","family":"Wainscott","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2180-2136","authenticated-orcid":true,"given":"Alex","family":"White","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7118-2326","authenticated-orcid":true,"given":"Brian A.","family":"Droz","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Stutsman","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron D.","family":"Showalter","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1242-9295","authenticated-orcid":true,"given":"Todd M.","family":"Suter","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Dunbar","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1426-2127","authenticated-orcid":true,"given":"Brandy M.","family":"Snider","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2825-5270","authenticated-orcid":true,"given":"Libbey S.","family":"O\u2019Farrell","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Hewitt","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Craig","family":"Ruble","sequence":"additional","affiliation":[{"name":"Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah R.","family":"Padgett","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2425-7597","authenticated-orcid":true,"given":"Eric M.","family":"Woerly","sequence":"additional","affiliation":[{"name":"Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7367-0875","authenticated-orcid":true,"given":"Jeffrey A.","family":"Peterson","sequence":"additional","affiliation":[{"name":"Synthetic Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamer","family":"Coskun","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3158-7807","authenticated-orcid":true,"given":"Zhaomin","family":"Liu","sequence":"additional","affiliation":[{"name":"Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-5623","authenticated-orcid":true,"given":"David E.","family":"Coutant","sequence":"additional","affiliation":[{"name":"Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2531-7958","authenticated-orcid":true,"given":"Minrong","family":"Ai","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J.","family":"Emmerson","sequence":"additional","affiliation":[{"name":"Diabetes, Obesity and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8145-7947","authenticated-orcid":true,"given":"Panjamaporn","family":"Sangwung","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4260-2451","authenticated-orcid":true,"given":"Francis S.","family":"Willard","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indianapolis, IN 46285, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/1043-2760(93)90071-L"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2023.170939"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(87)91194-9"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/379069a0"},{"key":"e_1_3_2_6_2","first-page":"891","article-title":"Semaglutide and cardiovascular outcomes in patients with type 2 diabetes","volume":"376","author":"Marso S. 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Fields E. M. Woerly M. G. Bell K. W. Sloop J. D. Ho Advances Toward an Oral Non-Peptide Agonist of the GLP-1 Receptor (American Chemical Society 2023) vol. 58 pp. 107\u2013132.","DOI":"10.1021\/mc-2023-vol58.ch05"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0093746"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.regpep.2003.10.028"},{"key":"e_1_3_2_22_2","unstructured":"T. P. 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Branch D. Tward A. C. Kolstad V. Pulyadi J. T. Vogelstein Z. Wu M. Gallagher An optimized tissue clearing protocol for rat brain labeling imaging and high throughput analysis. bioRxiv 639674 [Preprint] (2021). https:\/\/doi.org\/10.1101\/639674.","DOI":"10.1101\/639674"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adp5765","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,18]],"date-time":"2024-12-18T19:00:21Z","timestamp":1734548421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adp5765"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,18]]},"references-count":45,"journal-issue":{"issue":"778","published-print":{"date-parts":[[2024,12,18]]}},"alternative-id":["10.1126\/scitranslmed.adp5765"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adp5765","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,18]]},"assertion":[{"value":"2024-04-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-24","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadp5765"}}