Abstract
Androgen receptor (AR) is a steroid hormone receptor that is activated by endogenous androgens, mainly testosterone and 5α- dihydrotestosterone (5α-DHT). AR is also an important drug target, and AR antagonists (antiandrogens) have been widely used for prostate cancer therapy. Antiandrogens currently available on the market are all small molecules that antagonize AR function via binding to the ligand binding domain (LBD). AR peptide antagonist has been proposed as a ‘mechanism-based’ approach to directly block AR function by interrupting AR-protein interactions from the surface of the receptor. Without targeting the rigid ligand binding pocket within LBD, peptide antagonists allow more flexibility in structure design, and are likely to provide more efficient and complete blockade of AR function as compared to small molecule antagonists. AR interacts with a variety of proteins, and the interaction may be mediated by different functional domains of the receptor. Although varieties of AR-protein interfaces might serve as the target for peptide antagonist, majority of ongoing research is still focusing on peptides that target the LBD, which is mainly due to the abundance of structural information revealed by crystal structures. This review gives an overview of the current research attempts to develop AR peptide antagonists, particularly peptide antagonists that target the LBD and N-terminal domain (NTD). The challenges and opportunities for future discovery and development of peptide antagonists are discussed as well.
Keywords: Androgen receptor, peptide antagonist
Current Pharmaceutical Design
Title: Peptide Antagonist of the Androgen Receptor
Volume: 16 Issue: 9
Author(s): Wenqing Gao
Affiliation:
Keywords: Androgen receptor, peptide antagonist
Abstract: Androgen receptor (AR) is a steroid hormone receptor that is activated by endogenous androgens, mainly testosterone and 5α- dihydrotestosterone (5α-DHT). AR is also an important drug target, and AR antagonists (antiandrogens) have been widely used for prostate cancer therapy. Antiandrogens currently available on the market are all small molecules that antagonize AR function via binding to the ligand binding domain (LBD). AR peptide antagonist has been proposed as a ‘mechanism-based’ approach to directly block AR function by interrupting AR-protein interactions from the surface of the receptor. Without targeting the rigid ligand binding pocket within LBD, peptide antagonists allow more flexibility in structure design, and are likely to provide more efficient and complete blockade of AR function as compared to small molecule antagonists. AR interacts with a variety of proteins, and the interaction may be mediated by different functional domains of the receptor. Although varieties of AR-protein interfaces might serve as the target for peptide antagonist, majority of ongoing research is still focusing on peptides that target the LBD, which is mainly due to the abundance of structural information revealed by crystal structures. This review gives an overview of the current research attempts to develop AR peptide antagonists, particularly peptide antagonists that target the LBD and N-terminal domain (NTD). The challenges and opportunities for future discovery and development of peptide antagonists are discussed as well.
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Cite this article as:
Gao Wenqing, Peptide Antagonist of the Androgen Receptor, Current Pharmaceutical Design 2010; 16 (9) . https://dx.doi.org/10.2174/138161210790963850
DOI https://dx.doi.org/10.2174/138161210790963850 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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