title: Design and synthesis of conformationally constrained glucagon-like peptide-1 derivatives with increased plasma stability and prolonged in vivo activity.
abstract: A series of conformationally constrained derivatives of glucagon-like peptide-1 (GLP-1) were designed and evaluated. By use of [Gly (8)]GLP-1(7-37)-NH2 (2) peptide as a starting point, 17 cyclic derivatives possessing i to i + 4, i to i + 5, or i to i + 7 side chain to side chain lactam bridges from positions 18 to 30 were prepared. The effect of a helix-promoting alpha-amino-isobutyric acid (Aib) substitution at position 22 was also evaluated. The introduction of i to i + 4 glutamic acid-lysine lactam constraints in c[Glu (18)-Lys (22)][Gly (8)]GLP-1(7-37)-NH2 (6), c[Glu (22)-Lys (26)][Gly (8)]GLP-1(7-37)-NH2 (10), and c[Glu (23)-Lys (27)][Gly (8)]GLP-1(7-37)-NH2 (11) resulted in potent functional activity and receptor affinities comparable to native GLP-1. Selected GLP-1 peptides were chemoselectively PEGylated in order to prolong their in vivo activity. PEGylated peptides [Gly (8),Aib (22)]GLP-1(7-37)-Cys ((PEG))-Ala-NH2 (23) and c[Glu (22)-Lys (26)][Gly (8)]GLP-1(7-37)-Cys ((PEG))-Ser-Gly-NH2 (24) retained picomolar functional potency and avid receptor binding properties. Importantly, PEGylated GLP-1 peptide 23 exhibited sustained in vivo efficacy with respect to blood glucose reduction and decreased body weight for several days in nonhuman primates.
authors.affiliation: Chemistry Research and Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. lesm@amgen.com
authors.forename: Les P
authors.initials: LP
authors.lastname: Miranda
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Winters
authors.forename: Colin V
authors.initials: CV
authors.lastname: Gegg
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Aral
authors.forename: Jason
authors.initials: J
authors.lastname: Long
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Diamond
authors.forename: Mark
authors.initials: M
authors.lastname: Guido
authors.forename: Shanaka
authors.initials: S
authors.lastname: Stanislaus
authors.forename: Mark
authors.initials: M
authors.lastname: Ma
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rose
authors.forename: Leszek
authors.initials: L
authors.lastname: Poppe
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Véniant
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008252:Macaca fascicularis; D051379:Mice; D008817:Mice, Mutant Strains; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010949:Plasma; D011092:Polyethylene Glycols / Q000737:chemistry; D011487:Protein Conformation; D011869:Radioligand Assay; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; D011092:Polyethylene Glycols; D052216:Glucagon-Like Peptide 1