美国斯坦福大学医学院Katrin J. Svensson团队近日取得一项新成果。经过不懈努力，他们的研究认为激素原裂解预测揭示了一种非肠促胰岛素抗肥胖肽。2025年3月5日出版的《自然》发表了这项成果。

在这里，该课题组人员以计算药物发现为主题，系统地绘制了2600多个以前未被表征的由激素原转化酶切割的人类蛋白水解肽片段，从而能够鉴定出新的生物活性肽。使用这种方法，研究团队鉴定了一个12聚肽，BRINP2相关肽（BRP）。在药理学上，BRP在小鼠和猪中减少食物摄入并表现出抗肥胖作用，而不会引起恶心或厌恶。从机制上讲，BRP给药触发中枢FOS激活，并独立于瘦素、GLP-1受体和黑素皮质素4受体。总之，这些数据介绍了一种识别新的生物活性肽的方法，并从药理学上确定BRP可能对体重的治疗性调节有重要作用。

研究人员表示，肽激素是一类具有药理活性的分子，在调节能量稳态中起着重要作用。激素原转化酶1/3（也称为PCSK1/3）代表了肽加工的关键酶机制，如治疗靶点胰高血糖素样肽1 (GLP-1)。然而，PCSK1产生的肽的全谱及其功能作用在很大程度上仍然未知。

附：英文原文

Title: Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide

Author: Coassolo, Laetitia, B. Danneskiold-Samse, Niels, Nguyen, Quennie, Wiggenhorn, Amanda, Zhao, Meng, Wang, David Cheng-Hao, Toomer, David, Lone, Jameel, Wei, Yichao, Patel, Aayan, Liparulo, Irene, Kavi, Deniz, Wat, Lianna W., Reghupaty, Saranya Chidambaranathan, Kim, Julie Jae, Asemi, Tina, Bielczyk-Maczynska, Ewa, Li, Veronica L., Moya-Garzon, Maria Dolores, Krentz, Nicole A. J., Stahl, Andreas, Chou, Danny Hung-Chieh, Luo, Liqun, Svensson, Katrin J.

Issue&Volume: 2025-03-05

Abstract: Peptide hormones, a class of pharmacologically active molecules, have a critical role in regulating energy homeostasis. Prohormone convertase 1/3 (also known as PCSK1/3) represents a key enzymatic mechanism in peptide processing, as exemplified with the therapeutic target glucagon-like peptide 1 (GLP-1)1,2. However, the full spectrum of peptides generated by PCSK1 and their functional roles remain largely unknown. Here we use computational drug discovery to systematically map more than 2,600 previously uncharacterized human proteolytic peptide fragments cleaved by prohormone convertases, enabling the identification of novel bioactive peptides. Using this approach, we identified a 12-mer peptide, BRINP2-related peptide (BRP). When administered pharmacologically, BRP reduces food intake and exhibits anti-obesity effects in mice and pigs without inducing nausea or aversion. Mechanistically, BRP administration triggers central FOS activation and acts independently of leptin, GLP-1 receptor and melanocortin 4 receptor. Together, these data introduce a method to identify new bioactive peptides and establish pharmacologically that BRP may be useful for therapeutic modulation of body weight.

DOI: 10.1038/s41586-025-08683-y

Source: https://www.nature.com/articles/s41586-025-08683-y