Development of Eppin as a Male Contraceptive

Eppin 作为男性避孕药的开发

• 批准号: 7770805
• 负责人: MICHAEL GENE ORAND
• 金额: $ 22.93万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770805
• 关键词: Amino Acids; Binding; Binding Sites; Biological Assay; Cells; Chemicals; Chemistry; Cherry - dietary; Collaborations; Computer Assisted; Data; Databases; Development; Ejaculation; Essential Amino Acids; Family Planning; Generations; Goals; Human; Hydrolysis; Libraries; Logistics; Male Contraceptions; Male Contraceptive Agents; Molecular Models; Monkeys; Mutate; Permeability; Pharmaceutical Chemistry; Principal Investigator; Process; Protein Fragment; Protocols documentation; Publications; Recombinants; Research; Research Infrastructure; Research Project Grants; Science; Screening procedure; Serine Protease; Site; Small Molecule Chemical Library; Specificity; Sperm Motility; Staging; Structure-Activity Relationship; Surface; System; Technology; Testing; Toxic effect; Vasectomy; Work; assay development; base; cheminformatics; compound A4; condoms; contraceptive target; data management; design; drug discovery; flexibility; improved; in vitro Assay; inhibitor/antagonist; lead series; male; model design; molecular modeling; novel; programs; sperm cell

DESCRIPTION (provided by applicant): The long-term goals of this research project are to develop eppin as a male contraceptive target. We have been studying the interaction of eppin with semenogelin on the human sperm surface, particularly with regard to the resumption of sperm motility following ejaculation. Since our publication in Science in 2004 on the complete and reversible contraception of male monkeys immunized to a high titer with eppin, we have been investigating eppin as a drugable target. This application presents the detailed steps necessary for developing a drugable compound that inhibits eppin semenogelin binding. When eppin semenogelin binding is blocked, sperm motility is effectively inhibited. This project will be in conjunction (subcontract) with the drug discovery research program at the BRITE center, NCCU. Specific aim #1 is the identification of novel, potent and highly specific inhibitors of eppin-semenogelin binding through directed library screening (hit generation). Based on our preliminary data on compound A4, this aim will test the hypothesis that more potent and specific inhibitor compounds of eppin-semenogelin binding can be identified. To identify inhibitors in this specific aim, 3 development units will be established to coordinate the research flow at the BRITE Center: (1) Assay Development Unit, (2) Assay Implementation Unit (3) Screening and HTS Unit. Specific aim #2 is the iterative improvement of initial hits identified in Specific Aim #1 with medicinal chemistry and molecular modeling (hit-to-lead optimization) to improve the potency, selectivity and cell permeability and to decrease the cell toxicity. Specific aim #2 will establish 2 working units: (1) The Chemistry Unit and (2) The Cheminformatics Unit. Specific aim #3 will better define the target site on eppin for semenogelin and compounds discovered in specific aims #1 and #2. Using the eppin-semenogelin in vitro assays, recombinant eppin protein fragments and eppin with mutated key amino acid residues will be used to better define the semenogelin (or compound, e.g., A4) binding site on eppin. This specific aim will test the hypothesis that defining exactly which eppin amino acids are essential for semenogelin and/or a target compound binding will enable us to refine the specificity of the compound. PUBLIC RELEVANCE: This research project seeks to develop a new non-steroidal male contraceptive that will allow males greater choices than condoms or vasectomy. Wide spread availability of male contraceptives will enhance family planning throughout the world.

描述(由申请者提供)：该研究项目的长期目标是将Eppin发展为男性避孕目标。我们一直在研究Eppin和精原蛋白在人类精子表面的相互作用，特别是关于射精后精子活力的恢复。自从我们在2004年的《科学》杂志上发表了关于用Eppin免疫高滴度的雄性猴子的完全和可逆避孕的文章以来，我们一直在研究Eppin作为可用药的靶标。本申请提供了开发抑制Eppin精胶结合的可药物化合物所需的详细步骤。当Eppin精胶结合被阻断时，精子的活力被有效地抑制。该项目将与NCCU BRITE中心的药物发现研究计划结合(转包)。具体目标#1是通过直接文库筛选(HIT生成)鉴定新的、有效的和高度特异的Eppin-Semenogelin结合抑制剂。基于我们对化合物A4的初步数据，这一目标将检验这样一种假设，即可以鉴定出更有效和特异的Eppin-精胶结合抑制剂化合物。为了确定这一具体目标中的抑制因素，将设立3个开发单位，以协调BRITE中心的研究流程：(1)分析开发单位，(2)分析实施单位，(3)筛选和高温超导单位。特定目标#2是利用药物化学和分子建模(点击到领先优化)对特定目标#1中确定的初始命中进行迭代改进，以提高效力、选择性和细胞渗透性，并降低细胞毒性。具体目标2将设立两个工作单位：(1)化学股和(2)化学信息学股。特定目标#3将更好地定义Eppin上的目标位置以及在特定目标#1和#2中发现的化合物。使用Eppin-Semenogelin体外分析，重组Eppin蛋白片段和带有突变关键氨基酸残基的Eppin将被用来更好地定义Eppin上的Semenogelin(或化合物，例如A4)结合位点。这一特定的目的将检验这样的假设，即准确定义哪些Eppin氨基酸是精胶蛋白和/或目标化合物结合所必需的，将使我们能够精炼化合物的特异性。 公共相关性：该研究项目寻求开发一种新的非类固醇男性避孕药，使男性有比避孕套或输精管结扎术更多的选择。男性避孕药具的广泛普及将促进全世界的计划生育。