Novel coumarin modified GLP‐1 derivatives with enhanced plasma stability and prolonged in vivo glucose‐lowering ability

• DOI: 10.1111/bph.12843
• Publication Date: 2014-07-15T19:21:35Z
• Authors: Jing Han; Lidan Sun; Xun Huang; Zheng Li; Chenyu Zhang; Hai Qian; Wenlong Huang
• Keywords: Conjugate; Human serum albumin

Background and Purpose The short biological half‐life limits the therapeutic use of glucagon‐like peptide‐1 ( GLP ‐1) chemical modification to improve interaction peptides with serum albumin represents an effective strategy develop long‐acting peptide analogues. Coumarin, a natural product, is known bind tightly plasma proteins possesses many activities. Therefore, we designed synthesized series coumarin‐modified ‐1 derivatives, hypothesizing that conjugation coumarin would retain effects prolong conjugates. Experimental Approach Four cysteine‐modified analogues (1–4) were prepared using G ly 8 ‐ ‐1(7–36)‐ NH 2 as starting point. These conjugated two maleimides yield eight compounds (conjugates 6–13) for testing. Activation human GLP‐1 receptors, stability enzymic inactivation in binding assessed vitro . In vivo , on oral glucose tolerance tests (OGTT) rats blood levels db/db mice studied. Key Results Most conjugates showed well preserved receptor activation efficacy, enhanced albumin‐binding properties improved conjugate 7 was selected undergo further assessment. rats, had longer circulating t 1/2 than exendin‐4 or liraglutide. A prolonged antidiabetic effect observed after OGTT hypoglycaemic mice. Conclusions Implications Cysteine‐specific offers useful approach development incretin‐based agents. Conjugate promising long‐lasting derivative deserving investigation.