A Biweekly GLP‐1R Agonist Designed With Drug‐Free Intervals for Enhanced Efficacy, Receptor Homeostasis and Gastrointestinal Tolerability
7 affiliations
- 1School of Pharmacy, Faculty of Medicine & Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery Macau University of Science and Technology Macau China
- 2Nanjing Chi Heal Biomedicine Technology Co., Ltd Nanjing China
- 3School of Biomedical Engineering, Division of Life Sciences and Medicine University of Science and Technology of China Hefei China
- 4Suzhou Institute for Advanced Research University of Science and Technology of China Suzhou China
- 5Department of Basic Medical Sciences Changsha Medical University Changsha Hunan China
- 6Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations Changsha Hunan China
- 7Faculty of Applied Sciences Macao Polytechnic University Macau China
Abstract
Aim: To develop a next‐generation, longer‐acting, more‐clinical‐benefits agonist to achieve sustained efficacy with improved tolerability.
Methods: 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.
Results: CT130 retained high GLP‑1R affinity (EC50 = 21 pM) and exhibited a prolonged half‑life (13.9 h, 1.4‑fold vs semaglutide). Biweekly CT130 outperformed weekly semaglutide in body weight reduction, glucose tolerance, TC, LDL‑C, body fat percentage and other metabolic indicators. Drug‑free intervals enabled near‑complete GLP‑1R recycling, termed “GLP‑1R recovery”, preserving receptor homeostasis, whereas semaglutide drove progressive internalization. CT130 also alleviated constipation risk (increased fecal water) and uniquely lowered cholesterol by suppressing SREBP‑2, 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 > 10% weight loss with good safety.
Conclusions: 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.
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BibTeX
@article{ding2026biweekly,
title = {{A Biweekly GLP‐1R Agonist Designed With Drug‐Free Intervals for Enhanced Efficacy, Receptor Homeostasis and Gastrointestinal Tolerability}},
author = {Wei Ding and Qing Liu and Qiong Luo and Xiaojun Yao and Xingxing Fan},
journal = {Diabetes, Obesity \& Metabolism},
year = {2026},
month = sep,
doi = {10.1111/dom.71304},
url = {https://doi.org/10.1111/dom.71304},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - A Biweekly GLP‐1R Agonist Designed With Drug‐Free Intervals for Enhanced Efficacy, Receptor Homeostasis and Gastrointestinal Tolerability
AU - Wei Ding
AU - Qing Liu
AU - Qiong Luo
AU - Xiaojun Yao
AU - Xingxing Fan
PY - 2026
DA - 2026/09/08
JO - Diabetes, Obesity & Metabolism
DO - 10.1111/dom.71304
UR - https://doi.org/10.1111/dom.71304
AB - Aim: To develop a next‐generation, longer‐acting, more‐clinical‐benefits agonist to achieve sustained efficacy with improved tolerability. Methods: 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. Results: CT130 retained high GLP‑1R affinity (EC50 = 21 pM) and exhibited a prolonged half‑life (13.9 h, 1.4‑fold vs semaglutide). Biweekly CT130 outperformed weekly semaglutide in body weight reduction, glucose tolerance, TC, LDL‑C, body fat percentage and other metabolic indicators. Drug‑free intervals enabled near‑complete GLP‑1R recycling, termed “GLP‑1R recovery”, preserving receptor homeostasis, whereas semaglutide drove progressive internalization. CT130 also alleviated constipation risk (increased fecal water) and uniquely lowered cholesterol by suppressing SREBP‑2, 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 > 10% weight loss with good safety. Conclusions: 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.
SN - 1462-8902
SN - 1463-1326
ER -