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 哺乳动物新鲜射出的精子不能使卵子受精。他们获得了 射精后数小时内的能力，因为它们通过女性生殖道， 这个过程被称为获能。可溶性腺苷酸环化酶（sAC：ADCY10）是一种非激素性的腺苷酸环化酶。 对精子获能和男性生育力至关重要的靶点。药理学sAC抑制剂阻断 精子在体外的功能和两个不同的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。在此测试中的总体假设 避孕研究中心（CRC）的研究表明，可以设计sAC抑制剂， 适当剂量以阻断精子功能，同时最小化不良副作用。我们有 最近鉴定的sAC的小分子活化剂，其通过外部调节结构域起作用， sAC的催化核心这些激活剂选择性地刺激精子中富集的sAC亚型。在 在这个避孕发展研究项目中，我们假设一种新的抑制剂， 与这些调节结构域结合，将通过选择性抑制sAC来阻止获能 精子的功能靶向调节结构域的sAC抑制剂将产生更少的不期望的 副作用.在这个项目中，我们提出了一种高通量的策略来识别小分子 其阻断精子sAC的激活并阻止获能。合适的调控域 sAC抑制剂将接受所述的优化周期和体内研究的管道 在本CRC项目1和2中。本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。