In:
ChemMedChem, Wiley, Vol. 10, No. 8 ( 2015-08), p. 1424-1434
Abstract:
The present study details the development of a family of novel D ‐Ala 8 glucagon‐like peptide‐1 (GLP‐1) peptide conjugates by site specific conjugation to an antithrombin III (ATIII) binding carrier pentasaccharide through tetraethylene glycol linkers. All conjugates were found to possess potent insulin‐releasing activity. Peptides with short linkers ( 〈 25 atoms) conjugated at Lys 34 and Lys 37 displayed strong GLP‐1 receptor (GLP‐1‐R) binding affinity. All D ‐Ala 8 GLP‐1 conjugates exhibited prominent glucose‐lowering action. Biological activity of the Lys 37 short‐linker peptide was evident up to 72 h post‐injection. In agreement, the pharmacokinetic profile of this conjugate ( t 1/2 , 11 h) was superior to that of the GLP‐1‐R agonist, exenatide. Once‐daily injection of the Lys 37 short‐linker peptide in ob / ob mice for 21 days significantly decreased food intake and improved HbA 1c and glucose tolerance. Islet size was decreased, with no discernible change in islet number. The beneficial effects of the Lys 37 short‐linker peptide were similar to or better than either exenatide or liraglutide, another GLP‐1‐R agonist. In conclusion, GLP‐1 peptides conjugated to an ATIII binding carrier pentasaccharide have a substantially prolonged bioactive profile compatible for possible once‐weekly treatment of type 2 diabetes in humans.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201500140
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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