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Improved GPCR ligands from nanobody tethering

Author

Listed:
  • 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)

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.

Suggested Citation

  • Ross W. Cheloha & Fabian A. Fischer & Andrew W. Woodham & Eileen Daley & Naomi Suminski & Thomas J. Gardella & Hidde L. Ploegh, 2020. "Improved GPCR ligands from nanobody tethering," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15884-8
    DOI: 10.1038/s41467-020-15884-8
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