| Author |
Quirino, Herlinda Sherwood, Lance Keeney, Michael Chen, Guohua Woods, Ashley K. Yang, Peng-yu Nunez, Vanessa Shen, Weijun Ghartey-tagoe, Esi Schultz, Peter G. Luo, Xiaozhou Welzel, Gus Zou, Huafei Ding, Zhongli Chao, Elizabeth Singh, Parminder |
| Description |
Author Affiliation: Yang PY ( Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037); Zou H ( California Institute for Biomedical Research, La Jolla, CA 92037); Chao E ( California Institute for Biomedical Research, La Jolla, CA 92037); Sherwood L ( California Institute for Biomedical Research, La Jolla, CA 92037); Nunez V ( California Institute for Biomedical Research, La Jolla, CA 92037); Keeney M ( Corium International, Inc., Menlo Park, CA 94025.); Ghartey-Tagoe E ( Corium International, Inc., Menlo Park, CA 94025.); Ding Z ( Corium International, Inc., Menlo Park, CA 94025.); Quirino H ( California Institute for Biomedical Research, La Jolla, CA 92037); Luo X ( Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037); Welzel G ( California Institute for Biomedical Research, La Jolla, CA 92037); Chen G ( Corium International, Inc., Menlo Park, CA 94025.); Singh P ( Corium International, Inc., Menlo Park, CA 94025.); Woods AK ( California Institute for Biomedical Research, La Jolla, CA 92037); Schultz PG ( Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037); Shen W ( California Institute for Biomedical Research, La Jolla, CA 92037); |
| Abstract |
Antidiabetic treatments aiming to reduce body weight are currently gaining increased interest. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist administered twice daily via s.c. injection, improves glycemic control, often with associated weight reduction. To further improve the therapeutic efficacy of exendin-4, we have developed a novel peptide engineering strategy that incorporates a serum protein binding motif onto a covalent side-chain staple and applied to the peptide to enhance its helicity and, as a consequence, its potency and serum half-life. We demonstrated that one of the resulting peptides, E6, has significantly improved half-life and glucose tolerance in an oral glucose tolerance test in rodents. Chronic treatment of E6 significantly decreased body weight and fasting blood glucose, improved lipid metabolism, and also reduced hepatic steatosis in diet-induced obese mice. Moreover, the high potency of E6 allowed us to administer this peptide using a dissolvable microstructure-based transdermal delivery system. Pharmacokinetic and pharmacodynamic studies in guinea pigs showed that a single 5-min application of a microstructure system containing E6 significantly improved glucose tolerance for 96 h. This delivery strategy may offer an effective and patient-friendly alternative to currently marketed GLP-1 injectables and can likely be extended to other peptide hormones. |
