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Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability.
Br J Pharmacol. 2014 Dec; 171(23):5252-64.BJ

Abstract

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 Gly8 -GLP-1(7-36)-NH2 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 t1/2 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.

Authors+Show Affiliations

Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25039358

Citation

Han, Jing, et al. "Novel Coumarin Modified GLP-1 Derivatives With Enhanced Plasma Stability and Prolonged in Vivo Glucose-lowering Ability." British Journal of Pharmacology, vol. 171, no. 23, 2014, pp. 5252-64.
Han J, Sun L, Huang X, et al. Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability. Br J Pharmacol. 2014;171(23):5252-64.
Han, J., Sun, L., Huang, X., Li, Z., Zhang, C., Qian, H., & Huang, W. (2014). Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability. British Journal of Pharmacology, 171(23), 5252-64. https://doi.org/10.1111/bph.12843
Han J, et al. Novel Coumarin Modified GLP-1 Derivatives With Enhanced Plasma Stability and Prolonged in Vivo Glucose-lowering Ability. Br J Pharmacol. 2014;171(23):5252-64. PubMed PMID: 25039358.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability. AU - Han,Jing, AU - Sun,Lidan, AU - Huang,Xun, AU - Li,Zheng, AU - Zhang,Chenyu, AU - Qian,Hai, AU - Huang,Wenlong, Y1 - 2014/09/05/ PY - 2013/08/28/received PY - 2014/02/04/revised PY - 2014/06/30/accepted PY - 2014/7/22/entrez PY - 2014/7/22/pubmed PY - 2015/8/15/medline SP - 5252 EP - 64 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 171 IS - 23 N2 - 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 Gly8 -GLP-1(7-36)-NH2 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 t1/2 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/25039358/Novel_coumarin_modified_GLP_1_derivatives_with_enhanced_plasma_stability_and_prolonged_in_vivo_glucose_lowering_ability_ L2 - https://doi.org/10.1111/bph.12843 DB - PRIME DP - Unbound Medicine ER -