Improved GPCR ligands from nanobody tethering.

Abstract:

:Antibodies conjugated to bioactive compounds allow targeted delivery of therapeutics to cell types of choice based on that antibody's specificity. Here we develop a new type of conjugate that consists of a nanobody and a peptidic ligand for a G protein-coupled receptor (GPCR), fused via their C-termini. We address activation of parathyroid hormone receptor-1 (PTHR1) and improve the signaling activity and specificity of otherwise poorly active N-terminal peptide fragments of PTH by conjugating them to nanobodies (VHHs) that recognize PTHR1. These C-to-C conjugates show biological activity superior to that of the parent fragment peptide in vitro. In an exploratory experiment in mice, a VHH-PTH peptide conjugate showed biological activity, whereas the corresponding free peptide did not. The lead conjugate also possesses selectivity for PTHR1 superior to that of PTH(1-34). This design approach, dubbed "conjugation of ligands and antibodies for membrane proteins" (CLAMP), can yield ligands with high potency and specificity.

journal_name

Nat Commun

journal_title

Nature communications

authors

Cheloha RW,Fischer FA,Woodham AW,Daley E,Suminski N,Gardella TJ,Ploegh HL

doi

10.1038/s41467-020-15884-8

subject

Has Abstract

pub_date

2020-04-29 00:00:00

pages

2087

issue

1

issn

2041-1723

pii

10.1038/s41467-020-15884-8

journal_volume

11

pub_type

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