Receptor selectivity from minimal backbone modification of a polypeptide agonist

Abstract

Human parathyroid hormone (PTH) and N-terminal fragments thereof activate two receptors, hPTHR1 and hPTHR2, which share ∼51% sequence similarity. A peptide comprising the first 34 residues of PTH is fully active at both receptors and is used to treat osteoporosis. We have used this system to explore the hypothesis that backbone modification of a promiscuous peptidic agonist can provide novel receptor-selective agonists. We tested this hypothesis by preparing a set of variants of PTH(1–34)-NH2 that contained a single β-amino-acid residue replacement at each of the first eight positions. These homologs, each containing one additional backbone methylene unit relative to PTH(1–34)-NH2 itself, displayed a wide range of potencies in cell-based assays for PTHR1 or PTHR2 activation. The β-scan series allowed us to identify two homologs, each containing two α→β replacements, that were highly selective, one for PTHR1 and the other for PTHR2. These findings suggest that backbone modification of peptides may provide a general strategy for achieving activation selectivity among polypeptide-modulated receptors, and that success requires consideration of both β2- and β3-residues, which differ in terms of side-chain location.

Recognition of Class II MHC Peptide Ligands That Contain β-Amino Acids

“…The demonstration that incorporation of a b-residue can abrogate TCR engagement without compromising MHC-II binding mirrors past findings with an MHC-II binding peptide derived from MOG (46). Past work has shown that b-residue incorporation can impart selectivity between receptor subtypes (68) and between distinct signaling pathways for a single receptor (69). The replacement of awith b-residues might therefore represent a general strategy for creating MHC-II binding peptides with unique functional profiles.…”

Ureidopeptide GLP-1 analogues with prolonged activity in vivo via signal bias and altered receptor trafficking

“…17 We therefore hypothesize that modifying the backbone of exenatide might improve its proteolytic stability and prolong its activity in vivo. However, backbone modications at the N-terminal part of incretins and other ligands of class B GPCRs have scarcely been reported 15,[18][19][20] which reects the difficulty to mimic the complex network of interactions in the binding pocket of the receptor transmembrane domain. 21 Herein we report the utilization of a ureido residue replacement at position 2 of GLP-1 analogues to improve their pharmacodynamic properties via selective enhancement of G protein-dependent cAMP signalling and altered GLP-1R trafficking.…”

Impact of Substitution Registry on the Receptor‐Activation Profiles of Backbone‐Modified Glucagon‐like Peptide‐1 Analogues

“…This strategy is appealing because α→β replacements inhibit proteolytic degradation, which leads to very short in vivo lifetimes for natural peptide hormones. We have previously discovered that α→β modifications can modulate receptor selectivity or signaling profile relative to an all‐α prototype …”