Premium
Novel coumarin modified GLP ‐1 derivatives with enhanced plasma stability and prolonged in vivo glucose‐lowering ability
Author(s) -
Han Jing,
Sun Lidan,
Huang Xun,
Li Zheng,
Zhang Chenyu,
Qian Hai,
Huang Wenlong
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12843
Subject(s) - conjugate , in vivo , chemistry , coumarin , in vitro , receptor , pharmacology , cysteine , biological activity , albumin , peptide , human serum albumin , biochemistry , medicine , biology , enzyme , mathematical analysis , mathematics , microbiology and biotechnology , organic chemistry
Background and Purpose The short biological half‐life limits the therapeutic use of glucagon‐like peptide‐1 ( GLP ‐1) and chemical modification to improve the interaction of peptides with serum albumin represents an effective strategy to develop long‐acting peptide analogues. Coumarin, a natural product, is known to bind tightly to plasma proteins and possesses many biological activities. Therefore, we designed and synthesized a series of coumarin‐modified GLP ‐1 derivatives, hypothesizing that conjugation with coumarin would retain the therapeutic effects and prolong the biological half‐life of the conjugates. Experimental Approach Four cysteine‐modified GLP ‐1 analogues (1–4) were prepared using G ly 8 ‐ GLP ‐1(7–36)‐ NH 2 peptide as a starting point. These analogues were conjugated with two coumarin maleimides to yield eight compounds (conjugates 6–13) for testing. Activation of human GLP‐1 receptors, stability to enzymic inactivation in plasma and binding to human albumin were assessed in vitro . In vivo , effects on oral glucose tolerance tests (OGTT) in rats and on blood glucose levels in db/db mice were studied. Key Results Most conjugates showed well preserved receptor activation efficacy, enhanced albumin‐binding properties and improved in vitro plasma stability and conjugate 7 was selected to undergo further assessment. In rats, conjugate 7 had a longer circulating t 1/2 than exendin‐4 or liraglutide. A prolonged antidiabetic effect of conjugate 7 was observed after OGTT in rats and a prolonged hypoglycaemic effect in db/db mice. Conclusions and Implications Cysteine‐specific coumarin conjugation with GLP ‐1 offers a useful approach to the development of long‐acting incretin‐based antidiabetic agents. Conjugate 7 is a promising long‐lasting GLP ‐1 derivative deserving further investigation.