Developing Male Contraceptives by Targeting ANT4

以 ANT4 为靶点开发男性避孕药

基本信息

批准号：
7770796
负责人：
Naohiro Terada
金额：
$ 23.5万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/7770796
关键词：
Adenine Nucleotide Translocase Affect Affinity Ants Apoptosis Binding Binding Sites Biological Chemicals Computer Analysis Computer Simulation Contraceptive Agents Contraceptive Usage Contraceptive methods Development Developmental Therapeutics Program Docking Electrostatics Energy Metabolism Eukaryota Fertility Germ Cells Glucose Glycolysis Histology Infertility Inner mitochondrial membrane Label Lead Liposomes Male Contraceptive Agents Male Infertility Mammals Measures Meiosis Mitochondria Modeling Molecular Molecular Weight Mus National Cancer Institute Nucleotides Oxidative Phosphorylation Performance Pharmaceutical Preparations Pilot Projects Positioning Attribute Principal Investigator Protein Isoforms Radio Religion and Spirituality Safety Screening procedure Somatic Cell Sperm Motility Spermatocytes Technology Testing Time Toxic effect base cell growth cell type combinatorial contraceptive target cost heuristics in vivo inhibitor/antagonist male meetings mouse model novel programs reconstitution simulation small molecule unintended pregnancy

项目摘要

DESCRIPTION (provided by applicant): The high rate of unintended pregnancy can be attributed to inadequate access to or use of contraceptives, or both. It is important to provide alternative choices for effective contraception to meet the needs of people with different ethnic, cultural, and religious values. Since male-directed contraceptive options are extremely limited, development of male contraceptives with safety, efficiency and cost-performance is particularly desired. Adenine nucleotide translocase (Ant) facilitates ADP/ATP exchange across the mitochondrial inner membrane, thus making it essential for energy metabolism in eukaryotes. Among the four isoforms (Ant1-4) found in mammals, Ant4 is exclusively expressed in male germ cells. Ant4 expression is particularly high during male meiosis and is essential for progression of male meiosis. Targeted depletion of Ant4 in mice results in male meiotic arrest and subsequent male infertility. Since exogenous inhibition of male meiosis is considered one of the best approaches to develop male contraceptives, here we attempt to develop chemical compounds which specifically target Ant4. Based on a predicted structural pocket unique to Ant4 at the ADP/ATP binding site, we hypothesize that small molecules which selectively inhibit Ant4 over other Ants can be identified by a molecular docking approach, and that the identified small molecules will inhibit male meiosis and fertility in vivo. We will test these hypotheses through following step-by-step specific aims, and overall aim to develop novel male contraceptives. 1) Using a molecular docking approach, we will initially screen 300,000 small molecules in silico that potentially bind to and inhibit Ant4. 2) The 300 highest-scoring compounds will be screened for their ability to inhibit sperm motility in non-glycolytic conditions. 3) Biologically active compounds will then be tested for their ability to inhibit ADP/ATP exchange through Ant4. 4) The compounds will also be tested for the ability to inhibit male meiosis and fertility in vivo. 5) Further, the most promising lead compounds will be subjected to automated combinatorial optimization. PUBLIC RELEVANCE: This study has the potential to identify lead compounds and to ultimately develop novel male contraceptives that selectively eliminate male meiotic spermatocytes without damaging other cell types in the body.

描述（由申请人提供）：意外怀孕的高率可能归因于避孕药具的访问或使用不足或两者兼而有之。重要的是提供有效避孕的其他选择，以满足具有不同种族，文化和宗教价值观的人们的需求。由于男性指导的避孕药具非常有限，因此特别需要具有安全性，效率和成本效果的男性避孕药的发展。腺嘌呤核苷酸易位酶（ANT）促进了跨线粒体内膜的ADP/ATP交换，因此使其对于真核生物的能量代谢至关重要。在哺乳动物中发现的四种同工型（ANT1-4）中，ANT4仅在男性生殖细胞中表达。在男性减数分裂过程中，ANT4表达特别高，对于男性减数分裂的进展至关重要。小鼠中ANT4的靶向耗竭会导致男性减数分裂停滞和随后的男性不育症。由于外源抑制男性减数分裂是开发男性避孕药的最佳方法之一，因此我们在这里尝试开发专门针对ANT4的化合物。基于ADP/ATP结合位点ANT4独有的预测结构口袋，我们假设可以通过分子对接方法鉴定出选择性抑制ANT4的小分子，并且可以通过分子对接方法鉴定出，并且所鉴定的小分子将抑制男性的减数分裂和体内生育能力。我们将通过以下分步特定的目的来检验这些假设，并总体而开发新的男性避孕药。 1）使用分子对接方法，我们最初将筛选有可能结合并抑制ANT4的硅中的300,000个小分子。 2）将筛选300个得分最高的化合物在非糖酵解条件下抑制精子运动的能力。 3）然后将测试生物活性化合物，以抑制ANT4抑制ADP/ATP交换的能力。 4）还将测试化合物的体内抑制男性减数分裂和生育能力的能力。 5）此外，最有希望的铅化合物将受到自动组合优化。公众相关性：这项研究有可能识别铅化合物，并最终开发出新颖的男性避孕药，从而有选择地消除男性减数分裂精子细胞而不会损害体内其他细胞类型。