Improved GPCR ligands from nanobody tethering

Ross W. Cheloha, Fabian A. Fischer, Andrew W. Woodham, Eileen Daley, Naomi Suminski, Thomas J. Gardella () and Hidde L. Ploegh ()
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Ross W. Cheloha: 1 Blackfan Circle
Fabian A. Fischer: 1 Blackfan Circle
Andrew W. Woodham: 1 Blackfan Circle
Eileen Daley: 50 Blossom Street
Naomi Suminski: 1 Blackfan Circle
Thomas J. Gardella: 50 Blossom Street
Hidde L. Ploegh: 1 Blackfan Circle

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15884-8

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DOI: 10.1038/s41467-020-15884-8

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