1. Academic Validation
  2. Structure-activity studies of lGnRH-III through rational amino acid substitution and NMR conformational studies

Structure-activity studies of lGnRH-III through rational amino acid substitution and NMR conformational studies

  • Biopolymers. 2012;98(6):525-34. doi: 10.1002/bip.22123.
Eleni V Pappa 1 Aikaterini A Zompra Zoi Diamantopoulou Zinovia Spyranti George Pairas Fotini N Lamari Panagiotis Katsoris George A Spyroulias Paul Cordopatis
Affiliations

Affiliation

  • 1 Department of Pharmacy, University of Patras, Greece. el2pappa@yahoo.gr
Abstract

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.

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