Zong Leilei, Zhang Zhoudong, Li Xionghao, Jia Jie, Jiang Xiaohui, Wang Zitong, Liu Wenlang, Shen Xinyi, Feng Xiangyang, Huang Yangqing, Ding Haifeng, Song Yunsong, Zheng Zheng, Yuan Jiandong, Li Huanqiu
Jiang Su Key Laboratory of Antibody-Targeted Drug Research, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, P. R. China.
BrightGene Bio-Medical Technology Co., Ltd, Suzhou, Jiangsu 215000, P. R. China.
J Med Chem. 2025 Jul 24;68(14):14907-14918. doi: 10.1021/acs.jmedchem.5c01120. Epub 2025 Jul 3.
Parallel activation of the calcitonin receptor (CTR) and amylin receptor (AMYR) is considered a more effective weight-loss strategy. Although the novel dual amylin and calcitonin receptor agonist (DACRA), petrelintide, is currently undergoing phase II clinical trials, its agonistic activity remains insufficient compared with natural agonists. Further optimization of the agonistic capabilities of petrelintide is an attractive strategy for developing DACRAs. Due to the lack of structure-activity relationship (SAR) and target binding information, a step-by-step process involving three rounds of modifications was performed guided by structure-based drug design and molecular dynamics (MD) simulations. Two successful methylation strategies led to the identification of the more efficient novel DACRA, BGM1812, with excellent performance in terms of half-life, stability, and solubility. In both in vivo and in vitro studies, BGM1812 showed significantly enhanced efficacy. This finding provides valuable insights into the SAR of petrelintide and highlights the potential of BGM1812 as a promising obesity drug candidate.
降钙素受体（CTR）和胰淀素受体（AMYR）的平行激活被认为是一种更有效的减肥策略。尽管新型双靶点（胰淀素和降钙素）受体激动剂（DACRA）petrelintide目前正在进行II期临床试验，但其激动活性与天然激动剂相比仍不足。进一步优化petrelintide的激动能力是开发DACRA的一个有吸引力的策略。由于缺乏构效关系（SAR）和靶点结合信息，在基于结构的药物设计和分子动力学（MD）模拟的指导下，进行了一个包括三轮修饰的逐步过程。两种成功的甲基化策略导致了更有效的新型DACRA BGM1812的鉴定，其在半衰期、稳定性和溶解性方面具有优异的性能。在体内和体外研究中，BGM1812均显示出显著增强的疗效。这一发现为petrelintide的构效关系提供了有价值的见解，并突出了BGM1812作为一种有前景的肥胖症候选药物的潜力。
