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Optimization of Peptide Linker-Based Fluorescent Ligands for the Histamine H1 Receptor

Kok, Zhi Yuan; Stoddart, Leigh A.; Mistry, Sarah J.; Mocking, Tamara A.M.; Vischer, Henry F.; Leurs, Rob; Hill, Stephen J.; Mistry, Shailesh N.; Kellam, Barrie

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Authors

Zhi Yuan Kok

Leigh A. Stoddart

Sarah J. Mistry

Tamara A.M. Mocking

Henry F. Vischer

Rob Leurs

STEPHEN HILL STEVE.HILL@NOTTINGHAM.AC.UK
Professor of Molecular Pharmacology

Profile image of BARRIE KELLAM

BARRIE KELLAM BARRIE.KELLAM@NOTTINGHAM.AC.UK
Professor of Medicinal Chemistry



Abstract

The histamine H1 receptor (H1R) has recently been implicated in mediating cell proliferation and cancer progression, therefore high affinity H1R-selective fluorescent ligands are desirable tools for further investigation of this behaviour in vitro and in vivo. We previously reported a H1R fluorescent ligand, bearing a peptide-linker, based on antagonist VUF13816 and sought to further explore structure-activity relationships (SARs) around the linker, orthostere and fluorescent moieties. Here, we report a series of high affinity H1R fluorescent ligands varying in peptide linker composition, orthosteric targeting moiety and fluorophore. Incorporation of a boron-dipyrromethene (BODIPY) 630/650™-based fluorophore conferred high binding affinity to our H1R fluorescent ligands, remarkably overriding linker SAR observed in corresponding unlabeled congeners. Compound 31a, both potent and subtype-selective, enabled H1R visualization using confocal microscopy at a concentration of 10 nM. Molecular docking of 31a with the human H1R predicts the optimized peptide linker makes interactions with key residues in the receptor.

Citation

Kok, Z. Y., Stoddart, L. A., Mistry, S. J., Mocking, T. A., Vischer, H. F., Leurs, R., …Kellam, B. (2022). Optimization of Peptide Linker-Based Fluorescent Ligands for the Histamine H1 Receptor. Journal of Medicinal Chemistry, 65(12), 8258–8288. https://doi.org/10.1021/acs.jmedchem.2c00125

Journal Article Type Article
Acceptance Date Apr 11, 2022
Online Publication Date Jun 3, 2022
Publication Date Jun 23, 2022
Deposit Date Apr 28, 2022
Publicly Available Date Apr 28, 2022
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 65
Issue 12
Pages 8258–8288
DOI https://doi.org/10.1021/acs.jmedchem.2c00125
Public URL https://nottingham-repository.worktribe.com/output/7837708
Publisher URL https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.2c00125
Additional Information PMCID# PMC9234962

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