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。反复使用强效和长效的GnRH激动剂可通过脱敏GnRH受体来抑制性腺功能。这种特性在临床上用于前列腺癌的治疗，例如治疗子宫内膜异位症和体外受精。最近还发现了有效的促性腺激素释放激素多肽拮抗剂，它们比激动剂对促性腺激素具有中等和更深的抑制作用，从而为前者用于男性避孕打开了大门。这些多肽都不是口服有效的，多肽GnRH激动剂和拮抗剂在结构上是非常不同的。虽然GnRH激动剂在受体上的构象尚不清楚，但我们已经证明GnRH拮抗剂中的几个共价限制[环状(4-10)，环状(5-8)和环状(1-5)]与高亲和力和体内效力是相容的。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，该模型被用于成功地设计基于三氨基甘氨酸的生物活性文库。此外，该模型有助于确定假定与有效的非肽配体(T-98475)的元件一一对应。我们还成功地在几个GnRH拮抗剂结构中引入了尿素功能，导致了高亲和力和延长作用时间，表明分子间/分子内氢键相互作用在多肽的稳定性、溶解性和分布中起着重要作用。在这些结果的基础上，我们建议检验四个假设：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的生物活性构象并保持生物活性；B.GnRH拮抗剂共识模型将用于设计含有氨基甘氨酸支架的GnRH模拟小肽配体(BEID)，C.将在BEID中引入GnRH中的官能团，而不是GnRH拮抗剂中的官能团，以展示第一个类肽GnRH激动剂和关于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。学术研究人员目前还不能获得这样的分子。与过去二十年一样，将启动与学术同行的合作，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.