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Backbone modification of a polypeptide drug alters duration of action in vivo.

ABSTRACT: Systematic modification of the backbone of bioactive polypeptides through ?-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 ??? residue replacement that enables both high activity and improved pharmacokinetic properties in vivo.

SUBMITTER: Cheloha RW

PROVIDER: S-EPMC4205942 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Backbone modification of a polypeptide drug alters duration of action in vivo.

Cheloha Ross W RW Maeda Akira A Dean Thomas T Gardella Thomas J TJ Gellman Samuel H SH

Nature biotechnology 20140615 7

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. ...[more]

PMID: 24929976

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