Zhi Yuan Kok
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
Authors
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
Dr SHAILESH MISTRY Shailesh.Mistry@nottingham.ac.uk
Associate Professor
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 |
Files
acs.jmedchem.2c00125
(8.7 Mb)
PDF
Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
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