{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T07:07:16Z","timestamp":1788937636038,"version":"build-2803163510"},"reference-count":91,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>To develop a next\u2010generation, longer\u2010acting, more\u2010clinical\u2010benefits agonist to achieve sustained efficacy with improved tolerability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>CT130 was designed from semaglutide. Binding affinity was validated via molecular dynamics and cellular assays. Pharmacokinetics were profiled in SD rats; metabolic efficacy was evaluated in B6\/ob and DIO mice (CT130 biweekly vs semaglutide weekly). Receptor trafficking dynamics and cholesterol regulation were dissected mechanistically. Toxicology was assessed in rodents and a primate pilot study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CT130 retained high GLP\u20111R affinity (EC\n                      <jats:sub>50<\/jats:sub>\n                      \u2009=\u200921 pM) and exhibited a prolonged half\u2011life (13.9\u2009h, 1.4\u2011fold vs semaglutide). Biweekly CT130 outperformed weekly semaglutide in body weight reduction, glucose tolerance, TC, LDL\u2011C, body fat percentage and other metabolic indicators. Drug\u2011free intervals enabled near\u2011complete GLP\u20111R recycling, termed \u201cGLP\u20111R recovery\u201d, preserving receptor homeostasis, whereas semaglutide drove progressive internalization. CT130 also alleviated constipation risk (increased fecal water) and uniquely lowered cholesterol by suppressing SREBP\u20112, which upregulated LDLR while decoupling from PCSK9 induction, thereby promoting fecal cholesterol excretion without altering bile acid flux. No pathological changes were observed even at tens to 200 times the semaglutide dose. In monkeys, two biweekly doses induced &gt;\u200910% weight loss with good safety.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CT130 is a safe, once biweekly preclinical candidate that incorporates drug free intervals to allow GLP 1R restore. It delivers robust, lasting metabolic benefits with improved gastrointestinal tolerability, and offering a template for next generation long acting GLP 1R agonists.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.71304","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T06:44:48Z","timestamp":1788936288000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Biweekly\n                    <scp>GLP<\/scp>\n                    \u2010\n                    <scp>1R<\/scp>\n                    Agonist Designed With Drug\u2010Free Intervals for Enhanced Efficacy, Receptor Homeostasis and Gastrointestinal Tolerability"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7483-5584","authenticated-orcid":false,"given":"Wei","family":"Ding","sequence":"first","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine &amp; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery Macau University of Science and Technology  Macau China"},{"name":"Nanjing Chi Heal Biomedicine Technology Co., Ltd  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0773-3843","authenticated-orcid":false,"given":"Qing","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Division of Life Sciences and Medicine University of Science and Technology of China  Hefei China"},{"name":"Suzhou Institute for Advanced Research University of Science and Technology of China  Suzhou China"},{"name":"Department of Basic Medical Sciences Changsha Medical University  Changsha Hunan China"},{"name":"Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6130-2033","authenticated-orcid":false,"given":"Qiong","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences Changsha Medical University  Changsha Hunan China"},{"name":"Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations  Changsha Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9958-8438","authenticated-orcid":false,"given":"Xiaojun","family":"Yao","sequence":"additional","affiliation":[{"name":"Faculty of Applied Sciences Macao Polytechnic University  Macau China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7751-7193","authenticated-orcid":false,"given":"Xingxing","family":"Fan","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Faculty of Medicine &amp; Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery Macau University of Science and Technology  Macau China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"issue":"8","key":"e_1_2_13_2_1","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/s41573-025-01183-8","article-title":"GLP\u20101\u2010Based Therapies for Diabetes, Obesity and Beyond","volume":"24","author":"Drucker D. 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