Single Amino Acid Replacement in G‐7039 Leads to a 70‐fold Increase in Binding toward GHS‐R1a

The growth hormone secretagogue receptor type 1a (GHS‐R1a) is a class A rhodopsin‐like G protein coupled receptor (GPCR) that is expressed in a variety of human tissues and is differentially expressed in benign and malignant prostate cancer. Previously, the peptidomimetic [1‐Nal4,Lys5(4‐fluorobenzoy...

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Bibliographic Details
Published in:ChemMedChem 2019-10, Vol.14 (20), p.1762-1766
Main Authors: Lalonde, Tyler, Fowkes, Milan M., Hou, Jinqiang, Thibeault, Pierre E., Milne, Mark, Dhanvantari, Savita, Ramachandran, Rithwik, Luyt, Leonard G.
Format: Article
Language:English
Subjects:
Acids
Affinity
Amino acids
Binding
G protein-coupled receptors
ghrelin
Growth hormone
growth hormone secretagogue receptor
Human tissues
lipophilicity
Menopause
Molecular docking
partial agonists
peptidomimetics
Positron emission
Positron emission tomography
Prostate cancer
Radiochemistry
Rhodopsin
Tomography
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Summary:The growth hormone secretagogue receptor type 1a (GHS‐R1a) is a class A rhodopsin‐like G protein coupled receptor (GPCR) that is expressed in a variety of human tissues and is differentially expressed in benign and malignant prostate cancer. Previously, the peptidomimetic [1‐Nal4,Lys5(4‐fluorobenzoyl)]G‐7039 was designed as a molecular imaging tool for positron emission tomography (PET). However, this candidate was a poor binder (IC50=69 nm), required a lengthy four‐step radiosynthesis, and had a cLogP above 8. To address these challenges, we now report on changes targeted at the 4th position of G‐7039. A 2‐fluoropropionic acid (2‐FPA) group was added on to Lys5 to determine the potential binding affinity of the [18F]‐2‐FP radiolabeled analogue, which could be prepared by simplified radiochemistry. Lead candidate [Tyr4,Lys5(2‐fluoropropionyl)]G‐7039 exhibited an IC50 of 0.28 nm and low picomolar activity toward GHS‐R1a. Molecular docking revealed a molecular basis for this picomolar affinity. A potent fluorine‐containing ghrelin peptidomimetic: We discovered that tyrosine is a required amino acid at the 4th position of G‐7039 for improving both binding and potency, due to a unique hydrogen bond interaction that occurs between Tyr and Arg283. This chemical tool has potential applications in both imaging and therapy.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201900466