title: Backbone modification of a polypeptide drug alters duration of action in vivo.
abstract: Systematic modification of the backbone of bioactive polypeptides through β-amino acid residue incorporation could provide a strategy for generating molecules with improved drug properties, but such alterations can result in lower receptor affinity and potency. Using an agonist of parathyroid hormone receptor-1 (PTHR1), a G protein-coupled receptor in the B-family, we present an approach for α→β residue replacement that enables both high activity and improved pharmacokinetic properties in vivo.
authors.affiliation: Department of Chemistry, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Ross W
authors.initials: RW
authors.lastname: Cheloha
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dean
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gardella
authors.affiliation: Department of Chemistry, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D019943:Amino Acid Substitution; D000596:Amino Acids / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D008297:Male; D008657:Metabolic Clearance Rate; D008810:Mice, Inbred C57BL; D036361:Peptide Hormones / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000596:Amino Acids; C473449:PTH1R protein, human; D036361:Peptide Hormones; D044168:Receptor, Parathyroid Hormone, Type 1