Zeng Zhipeng, Tan Runcheng, Chen Shi, Chen Haolin, Liu Zhijia, Liu Lixin, Li Mingqiang, Chen Yongming
Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China.
School of Materials Science and Engineering, Center of Functional Biomaterials, Key Laboratory of Polymeric Composite Materials and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou 510275, China.
Acta Pharm Sin B. 2024 Jun;14(6):2761-2772. doi: 10.1016/j.apsb.2024.02.022. Epub 2024 Mar 4.
Although the discovery of insulin 100 years ago revolutionized the treatment of diabetes, its therapeutic potential is compromised by its short half-life and narrow therapeutic index. Current long-acting insulin analogs, such as insulin-polymer conjugates, are mainly used to improve pharmacokinetics by reducing renal clearance. However, these conjugates are synthesized without sacrificing the bioactivity of insulin, thus retaining the narrow therapeutic index of native insulin, and exceeding the efficacious dose still leads to hypoglycemia. Here, we report a kind of di-PEGylated insulin that can simultaneously reduce renal clearance and receptor-mediated clearance. By impairing the binding affinity to the receptor and the activation of the receptor, di-PEGylated insulin not only further prolongs the half-life of insulin compared to classical mono-PEGylated insulin but most importantly, increases its maximum tolerated dose 10-fold. The target of long-term glycemic management has been achieved through improved pharmacokinetics and a high dose. This work represents an essential step towards long-acting insulin medication with superior safety in reducing hypoglycemic events.
尽管100年前胰岛素的发现彻底改变了糖尿病的治疗方式，但其治疗潜力因半衰期短和治疗指数窄而受到影响。目前的长效胰岛素类似物，如胰岛素-聚合物缀合物，主要用于通过减少肾脏清除率来改善药代动力学。然而，这些缀合物在合成时并未牺牲胰岛素的生物活性，因此仍保留了天然胰岛素狭窄的治疗指数，超过有效剂量仍会导致低血糖。在此，我们报告了一种双聚乙二醇化胰岛素，它可以同时降低肾脏清除率和受体介导的清除率。通过削弱与受体的结合亲和力和受体的激活，双聚乙二醇化胰岛素与经典的单聚乙二醇化胰岛素相比，不仅进一步延长了胰岛素的半衰期，而且最重要的是，将其最大耐受剂量提高了10倍。通过改善药代动力学和高剂量实现了长期血糖管理的目标。这项工作代表了在降低低血糖事件方面具有卓越安全性的长效胰岛素药物迈出的重要一步。
