A Peptide Engineering Platform for Generating Stapled Long-acting Peptide Hormones
Weijun Shen
Principal Investigator, California Institute for Biomedical Research
As a drug class, peptides offer exquisite specificity and potency, but also present challenges associated with poor stability and short half-life, manifesting in the need for frequent injections, poor patient compliance, and overall compromised efficacy. Exendin-4, a glucagon-like peptide-1 receptor agonist administered twice daily via subcutaneous 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 (OGTT) in rodents. Chronic treatment of E6 significantly decreased body weight and fasting blood glucose, improved lipid metabolism and also reduced hepatic steatosis in DIO mice. Moreover, the high potency of E6 allowed us to administer this peptide using a novel 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 hours. This delivery strategy may offer an effective and patient-friendly alternative to currently marketed GLP-1 injectables. Current progress in applying this half-life extension strategy to other peptide hormones will also be discussed. References: Peng-Yu Yang, Huafei Zou, Elizabeth Chao, Lance Sherwood, Vanessa Nunez, Michael Keeney, Esi Ghartey-Tagoe, Zhongli Ding, Herlinda Quirino, Xiaozhou Luo, Gus Welzel, Guohua Chen, Parminder Singh, Ashley K. Woods*, Peter G. Schultza* and Weijun Shen* Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery, Proc Natl Acad Sci USA 2016, Early EditionAvinash Muppidi, Huafei Zou, Elizabeth Chao, Pengyu Yang, Lance Sherwood, Vanessa Nunez, Ashley Woods, Peter G Schultz*, Qing Lin* , Weijun Shen* “Design of potent, proteolytically stable oxyntomodulin analogs” ACS Chem Biol 2016,11(2):324-8