Gamete surface metalloproteinases as contraceptive targets

配子表面金属蛋白酶作为避孕靶点

• 批准号: 6611184
• 负责人: Diana G Myles
• 金额: $ 16.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-12 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611184
• 关键词: Macaca fascicularis; contraceptives; cooperative study; drug design /synthesis /production; drug screening /evaluation; enzyme activity; fertility immunology; fertilization; laboratory mouse; metalloendopeptidases; protease inhibitor; sperm

DESCRIPTION (provided by applicant): This project is focused on identifying a surface metalloprotease, specifically expressed on sperm or eggs, that is essential for conception and developing a contraceptive agent that acts as a specific inhibitor of this metalloprotease. Metalloprotease inhibitors are currently used as drugs and more are being developed to treat a variety of human disorders. In our research we have recently made two discoveries that serve as the basis for each of the two aims of this proposal. Specific Aim 1. Develop a metalloprotease inhibitor as a contraceptive agent that blocks the function of sperm-specific ADAM proteases (testases). We have found that there is a subfamily of the ADAM family of proteins called the testases. These proteins have a metalloprotease consensus active site, indicating they have enzyme activity; their expression is confined to the testis. We will test the hypothesis that testases have a required role, or perhaps more than one role, in sperm development, maturation or in sperm function. We will then proceed toward development of a metalloprotease inhibitor that blocks testase activity and can be used as a contraceptive agent. Specific Aim 2. Develop a metalloprotease inhibitor as a contraceptive agent that blocks sperm- egg fusion. We also found that there is a metalloprotease, apparently required for mammalian sperm-egg fusion, present on either the sperm or the egg surface. In Aim 2 we propose to identify that metalloprotease activity. We will test if it is an ADAM protease or matrix metalloprotease (MMP) on the egg or the sperm. If the protease is a sperm ADAM (i.e., a testase), Aims 1 and 2 will intersect. Once a unique metalloprotease is identified, we will test for tissue specificity and proceed toward development of a drug that will act as an inhibitor for that specific metalloprotease activity.

描述(由申请者提供)：这个项目的重点是识别表面 金属蛋白酶，在精子或卵子上特异表达，对受孕和 开发一种避孕药，作为这种金属蛋白酶的特异性抑制剂。 金属蛋白酶抑制剂目前被用作药物，更多的药物正在被开发用于治疗各种人类疾病。在我们的研究中，我们最近有了两个发现，这两个发现是这项提议的两个目标的基础。 具体目的1.开发一种金属蛋白酶抑制剂，作为一种避孕剂，阻断精子特异性ADAM蛋白酶(Testase)的功能。我们已经发现，亚当蛋白质家族中有一个亚家族被称为测试酶。这些蛋白具有金属蛋白酶的共同活性部位，表明它们具有酶活性；它们的表达仅限于睾丸。我们将检验这一假设，即在精子发育、成熟或精子功能中具有必需的作用，或者可能不止一个作用。然后，我们将继续开发一种金属蛋白酶抑制剂，它可以阻断测试酶的活性，并可用作避孕药。 具体目的2.开发一种金属蛋白酶抑制剂，作为一种阻止精子-卵子融合的避孕剂。我们还发现，在精子或卵子表面都存在一种金属蛋白酶，这显然是哺乳动物精子与卵子融合所必需的。在目标2中，我们建议鉴定金属蛋白酶活性。我们将测试它是否是卵子或精子上的亚当蛋白酶或基质金属蛋白酶(MMPs)。如果该酶是精子亚当(即测试酶)，则目标1和目标2将相交。一旦确定了一种独特的金属蛋白酶，我们将测试组织特异性，并继续开发一种药物，该药物将作为该特定金属蛋白酶活性的抑制剂。