title: Engineering a long-acting, potent GLP-1 analog for microstructure-based transdermal delivery.
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.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Peng-Yu
authors.initials: PY
authors.lastname: Yang
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Huafei
authors.initials: H
authors.lastname: Zou
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chao
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Lance
authors.initials: L
authors.lastname: Sherwood
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Vanessa
authors.initials: V
authors.lastname: Nunez
authors.affiliation: Corium International, Inc., Menlo Park, CA 94025.
authors.forename: Michael
authors.initials: M
authors.lastname: Keeney
authors.affiliation: Corium International, Inc., Menlo Park, CA 94025.
authors.forename: Esi
authors.initials: E
authors.lastname: Ghartey-Tagoe
authors.affiliation: Corium International, Inc., Menlo Park, CA 94025.
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Ding
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Herlinda
authors.initials: H
authors.lastname: Quirino
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Luo
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Gus
authors.initials: G
authors.lastname: Welzel
authors.affiliation: Corium International, Inc., Menlo Park, CA 94025.
authors.forename: Guohua
authors.initials: G
authors.lastname: Chen
authors.affiliation: Corium International, Inc., Menlo Park, CA 94025.
authors.forename: Parminder
authors.initials: P
authors.lastname: Singh
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037; awoods@calibr.org schultz@scripps.edu wshen@calibr.org.
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Woods
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; California Institute for Biomedical Research, La Jolla, CA 92037; awoods@calibr.org schultz@scripps.edu wshen@calibr.org.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037; awoods@calibr.org schultz@scripps.edu wshen@calibr.org.
authors.forename: Weijun
authors.initials: W
authors.lastname: Shen
mesh_terms: D000279:Administration, Cutaneous; D000595:Amino Acid Sequence; D001835:Body Weight; D002942:Circular Dichroism; D000242:Cyclic AMP / Q000096:biosynthesis; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006801:Humans; D015202:Protein Engineering
chemical_list: D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP
keywords: GLP-1 receptor agonist; half-life extension; helix stabilization; lipidated cross-linker; microstructure array