Di-PEGylated insulin:A long-acting insulin conjugate with superior safety in reducing hypoglycemic events  

作　　者：Zhipeng Zeng Runcheng Tan Shi Chen Haolin Chen Zhijia Liu Lixin Liu Mingqiang Li Yongming Chen 

机构地区：[1]Laboratory of Biomaterials and Translational Medicine,Center for Nanomedicine,The Third Affiliated Hospital,Sun Yat-sen University,Guangzhou 510630,China [2]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

出　　处：《Acta Pharmaceutica Sinica B》2024年第6期2761-2772,共12页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.51820105004,China);the Key Areas Research and Development Program of Guangzhou(No.202007020006,China).

摘　　要：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 in vivo 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.

关 键 词：Diabetes INSULIN Therapeutic index HYPOGLYCEMIA PEGYLATION Receptor-mediated clearance HALF-LIFE Diabetic nephropathy 

分 类 号：R965[医药卫生—药理学]