Development of regulatory domain inhibitors of ADCY10

ADCY10调控域抑制剂的开发

• 批准号: 10017319
• 负责人: LONNY R LEVIN
• 金额: $ 35.79万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10017319
• 关键词: Acute; Adenylate Cyclase; Adverse effects; Affect; Alternative Splicing; Bicarbonates; Binding; Biochemical; Catalytic Domain; Chemicals; Chronic; Cloning; Code; Complementary DNA; Contraceptive Agents; Contraceptive methods; Core Facility; Cyclic AMP; Cytosol; Data; Development; Dose; Ejaculation; Event; Exhibits; Exons; Exposure to; Female; Fertility; Genes; Genetic; Goals; Heme; Hour; Human; In Vitro; Injections; Knockout Mice; Laboratories; Lead; Length; Mediating; Mouse Strains; Mus; Oral; Oral Contraceptives; Pharmacology; Phenotype; Physiological Processes; Process; Production; Protein Isoforms; Proteins; Rattus; Recording of previous events; Research; Research Project Grants; Rodent; Seminal fluid; Series; Signal Transduction; Spectrum Analysis; Sperm Capacitation; Sterility; Structure; Testing; Testis; Time; Work; appropriate dose; contraceptive efficacy; counterscreen; design; experimental study; functional restoration; high throughput screening; in vivo; inhibitor/antagonist; loss of function; male; male fertility; novel strategies; prevent; reproductive tract; research and development; response; reversible contraceptive; screening; side effect; small molecule; sperm cell; sperm function; virtual; zygote

Project 3 Freshly ejaculated mammalian sperm are unable to fertilize an egg. They acquire fertilizing capacity in the hours following ejaculation, as they pass through the female reproductive tract, in a process known as capacitation. Soluble adenylyl cyclase (sAC: ADCY10) is a non-hormonal target essential for sperm capacitation and male fertility. Pharmacological sAC inhibitors block sperm functions in vitro and two distinct sAC knockout (KO) mouse strains exhibit male-specific sterility without exhibiting other overt phenotypes. The overall hypothesis tested in this Contraception Research Center (CRC) is that sAC inhibitors can be designed which can be appropriately dosed to block sperm functions while minimizing undesirable side effects. We have recently identified small molecule activators of sAC which function via regulatory domains outside sAC’s catalytic core. These activators selectively stimulate isoforms of sAC enriched in sperm. In this Contraception Development Research Project, we hypothesize that a new class of inhibitors, which binds to these regulatory domains, will prevent capacitation by selectively inhibiting sAC functions in sperm. Regulatory-domain targeting sAC inhibitors would produce fewer undesirable side effects. In this Project, we propose a high throughput strategy to identify small molecules which block the activation of sperm sAC and prevent capacitation. Suitable regulatory domain sAC inhibitors will be subjected to the pipeline of refinement cycles and in vivo studies described in Projects 1 and 2 of this CRC. The ultimate goal of this Project is to develop inhibitors selective for sAC isoforms in sperm as lead compounds for oral, non-hormonal contraceptives.

项目3 刚射出的哺乳动物精子无法使卵子受精。他们获得施肥 射精后数小时内，当它们通过女性生殖道时， 称为获能的过程。可溶性腺苷酸环化酶 (sAC: ADCY10) 是一种非激素 对精子获能和男性生育能力至关重要的目标。药理 sAC 抑制剂阻断 精子在体外功能和两种不同的 sAC 敲除 (KO) 小鼠品系表现出雄性特异性 不育而不表现出其他明显的表型。本次测试的总体假设 避孕研究中心（CRC）认为可以设计sAC抑制剂 适当剂量可阻止精子功能，同时最大限度地减少不良副作用。我们有 最近发现了 sAC 的小分子激活剂，其通过外部调节域发挥作用 sAC的催化核心。这些激活剂选择性地刺激精子中富含的 sAC 亚型。在 在这个避孕开发研究项目中，我们假设一类新的抑制剂， 与这些调节域结合，将通过选择性抑制 sAC 来防止获能 在精子中发挥作用。调节域靶向 sAC 抑制剂将产生更少的不良反应 副作用。在这个项目中，我们提出了一种高通量策略来识别小分子 阻止精子 sAC 的激活并防止获能。合适的监管领域 sAC 抑制剂将接受所述的细化循环和体内研究的管道 在本 CRC 的项目 1 和 2 中。该项目的最终目标是开发选择性抑制剂 精子中的 sAC 亚型作为口服非激素避孕药的先导化合物。