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

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
• 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