Structure-activity studies of lGnRH-III through rational amino acid substitution and NMR conformational studies
| Autor: | Zoi Diamantopoulou, Eleni V. Pappa, Fotini N. Lamari, Zinovia Spyranti, Paul Cordopatis, George Pairas, George Spyroulias, Panagiotis Katsoris, Aikaterini A. Zompra |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Stereochemistry Protein Conformation Biophysics Antineoplastic Agents Gonadotropin-releasing hormone Biochemistry Biomaterials Gonadotropin-Releasing Hormone Structure-Activity Relationship Protein structure Cell Line Tumor LNCaP Side chain Structure–activity relationship Humans Cell Proliferation chemistry.chemical_classification Chemistry Organic Chemistry Prostatic Neoplasms General Medicine Nuclear magnetic resonance spectroscopy Amino acid Pyrrolidonecarboxylic Acid Salt bridge |
| Zdroj: | Biopolymers. 98(6) |
| ISSN: | 0006-3525 |
| Popis: | Lamprey gonadotropin-releasing hormone type III (lGnRH-III) is an isoform of GnRH isolated from the sea lamprey (Petromyzon marinus) with negligible endocrine activity in mammalian systems. Data concerning the superior direct anticancer activity of lGnRH-III have been published, raising questions on the structure-activity relationship. We synthesized 21 lGnRH-III analogs with rational amino acid substitutions and studied their effect on PC3 and LNCaP prostate cancer cell proliferation. Our results question the importance of the acidic charge of Asp⁶ for the antiproliferative activity and indicate the significance of the stereochemistry of Trp in positions 3 and 7. Furthermore, conjugation of an acetyl-group to the side chain of Lys⁸ or side chain cyclization of amino acids 1-8 increased the antiproliferative activity of lGnRH-III demonstrating that the proposed salt bridge between Asp⁶ and Lys⁸ is not crucial. Conformational studies of lGnRH-III were performed through NMR spectroscopy, and the solution structure of GnRH-I was solved. In solution, lGnRH-III adopts an extended backbone conformation in contrast to the well-defined β-turn conformation of GnRH-I. |
| Databáze: | OpenAIRE |
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