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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Amino Acid Substitution
-
Amino Acids / chemistry
-
Amino Acids / pharmacokinetics
-
Animals
-
Male
-
Metabolic Clearance Rate
-
Mice, Inbred C57BL
-
Peptide Hormones / blood
-
Peptide Hormones / chemistry*
-
Peptide Hormones / pharmacokinetics*
-
Receptor, Parathyroid Hormone, Type 1 / antagonists & inhibitors*
-
Structure-Activity Relationship
-
Tissue Distribution
Substances
-
Amino Acids
-
PTH1R protein, human
-
Peptide Hormones
-
Receptor, Parathyroid Hormone, Type 1