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。重复使用强效长效GnRH激动剂通过GnRH受体脱敏抑制性腺功能。这种性质在临床上用于治疗前列腺癌，例如子宫内膜异位症和体外受精。最近还发现了有效的GnRH肽拮抗剂，其优点是比激动剂对促性腺激素具有中等和更深的抑制作用，因此为前者用于男性避孕打开了大门。这些肽都不是口服有效的，肽GnRH激动剂和拮抗剂在结构上非常不同。尽管对GnRH激动剂在受体上的构象一无所知，但我们已经证明GnRH拮抗剂中的几种共价约束[环（4-10）、环（5-8）和环（1-5）]与高亲和力和体内效力相容。这些类似物的NMR结构导致GnRH拮抗剂共识模型的确定，该模型用于成功设计基于生物活性三氨基甘氨酸的文库。此外，该模型有助于鉴定与有效非肽配体（T-98475）元素的假定一一对应关系。我们还成功地在几种GnRH拮抗剂结构中引入了尿素功能，导致高亲和力和延长的作用持续时间，这表明分子间/分子内氢键相互作用在肽稳定性，溶解度和分布中起着重要作用。在此基础上，我们提出了四个假设：A.在残基（1-5）、（4-10）和（5-8）上策略性地放置正电荷和负电荷将稳定GnRH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（betide）的小GnRH肽模拟配体，C。本文介绍了在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，以便为第一个肽模拟GnRH激动剂和对受体激活过程的结构见解，D。使用尿素官能团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起效。目前学术研究人员还无法获得这样的分子。与过去二十年一样，将启动与学术界同事的合作，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.