SYNTHETIC SUBSTANCES CONTROLLING REPRODUCTION

促性腺激素释放激素（GnRH）是生殖功能的关键调节因子。反复施用强效和长效GnRH激动剂可通过GnRH受体的脱敏抑制性腺功能。这种特性在临床上用于治疗前列腺癌、子宫内膜异位症和体外受精等。GnRH的强效肽拮抗剂最近也被发现，它们比激动剂具有中级和更深刻的促性腺激素抑制作用，从而为前者用于男性避孕打开了大门。这些肽都不是有效的口服，肽GnRH激动剂和拮抗剂是非常不同的结构。虽然GnRH激动剂在受体上的构象尚不清楚，但我们已经表明，GnRH拮抗剂中的几个共价约束条件[cyclo(4-10), cyclo（5-8）和cyclo(1-5)]具有高亲和力和体内效力。这些类似物的核磁共振结构导致了GnRH拮抗剂共识模型的确定，该模型用于成功设计生物活性三氨基甘氨酸库。此外，该模型有助于识别与强效非肽配体（T-98475）元素的假定一对一对应关系。我们还成功地在几种GnRH拮抗剂结构中引入尿素功能，导致高亲和力和延长作用时间，这表明分子间/分子内氢键相互作用在肽的稳定性，溶解度和分布中起重要作用。在这些结果的基础上，我们提出检验四个假设：A.在残基（1-5）、（4-10）和（5-8）上战略性地放置正电荷和负电荷将稳定GnRH的生物活性构象，并保留生物活性。B. GnRH拮抗剂共识模型将用于设计含有氨基甘氨酸支架的小GnRH拟肽配体（betide）。C.在GnRH中发现的功能基团，而不是在GnRH拮抗剂中发现的功能基团，将在betides中引入第一种肽类GnRH激动剂和受体激活过程的结构分析。D.利用尿素功能优化氢键相互作用，将产生安全和长期激活的GnRH拮抗剂，在短期和长期适应症中显示立即开始的作用。这种分子目前还没有提供给学术研究人员。与过去二十年一样，将启动与学术同事的合作，以最大限度地发挥这项研究的影响。

Gonadotropin releasing hormone (GnRH) is a key regulator of reproductive functions. Repeated administration of potent and long acting GnRH agonists inhibits gonadal functions through desensitization of the GnRH receptor. This property is used clinically for t he treatment of prostate cancers, managed of endometriosis and in vitro fertilization for example. Potent peptide antagonists of GnRH have also been identified recently that have the advantage of intermediate and more profound inhibition of gonadotropins than the agonists thus opening the door to the use of the former for male contraception. None of these peptides are potent orally, Peptide GnRH agonists and antagonists are very different structurally. Whereas nothing is known of the conformation of GnRH agonists at the receptor, we have shown that several covalent constraints [cyclo(4-10), cyclo(5-8) and cyclo(1-5)] in GnRH antagonists are compatible with high affinity and in vivo potency. The NMR structures of these analogs led to the determination of a GnRH antagonist consensus model that was used for the successful design of a bioactive tri-aminoglycine-based library. Additionally, this model was helpful in identifying a putative one-to-one correspondence with elements of a potent non-peptide ligand (T-98475). We have also successfully introduced urea function in several GnRH antagonist structures that resulted in high affinity and extended duration of action, suggesting an important role for inter/intramolecular hydrogen bonding interactions in peptide stability, solubility and distribution. One the basis of these results, we propose to test four hypotheses: A. Strategically placed positive and negative charges on residues (1-5), (4-10) and (5-8) will stabilize the GnRH bioactive conformation with retention of biological activity, B. The GnRH antagonist consensus model will be used for the design of small GnRH peptidomimetic ligands containing aminoglycine scaffolds (betide), C. Functional groups found in GnRH rather than in GnRH antagonists will be introduces in betides to field the first peptidomimetic GnRH agonist and structural insights on the process of receptor activation, D. Optimization of hydrogen bonding interactions using urea functionalities will yield safe and long activating GnRH antagonists that display immediate onset of action in short- and long-term indications. Such molecules are not presently available to academic researchers. As in the past twenty years, collaborations with academic colleagues will be initiated, to maximize the impact of this research.