Replacement of the C-terminal Trp-cage of Exendin-4 with a Fatty Acid Improves Therapeutic Utility.

Replacement of the C-terminal Trp-cage of Exendin-4 with a Fatty Acid Improves Therapeutic Utility. Biochem Pharmacol. 2018 Mar 06;: Authors: Gi Lee J, Ha Ryu J, Kim SM, Park MY, Kim SH, Shin YG, Sohn JW, Hyung Kim H, Park ZY, Young Seong J, Il Kim J Abstract Exendin-4, a 39 amino acid peptide isolated from the saliva of the Gila monster, plays an important role in regulating glucose homeostasis, and is used clinically for the treatment of type 2 diabetes. Exendin-4 shares 53% sequence identity with the incretin hormone glucagon-like peptide 1 (GLP-1) but, unlike GLP-1, is highly resistant to proteolytic enzymes such as dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase 24.11 (NEP 24.11). Herein, we focused on the structure and function of the C-terminal Trp-cage of exendin-4, and suggest that it may be structurally required for resistance to proteolysis by NEP 24.11. Using a series of substitutions and truncations of the C-terminal Trp-cage, we found that residues 1-33, including the N-terminal and helical regions of wild-type (WT) exendin-4, is the minimum motif required for both high peptidase resistance and potent activity toward the GLP-1 receptor comparable to WT exendin-4. To improve the therapeutic utility of C-terminally truncated exendin-4, we incorporated various fatty acids into exendin-4(1-33) in which Ser33 was substituted with Lys for acylation. Exendin-4 (1-32)K-capric acid exhibited the most well balanced act...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research