Targeting nuclear receptors with novel synthetic ligands

用新型合成配体靶向核受体

• 批准号: 6580-2009
• 负责人: Wright, James
• 金额: $ 1.09万
• 依托单位: Carleton University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2009
• 资助国家: 加拿大
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=420272
• 关键词: Targeting; nuclear; receptors; novel; synthetic

My proposal consists of three parts, all related to the general area of pharmaceutical drug design. Part I. Improving the calculation of the binding affinity of a drug to a protein target. Part II. Creating a complete set of agonists and antagonists for the estrogen receptor. Part III. Creating an improved form of "peptide patch" to block the activation of the estrogen receptor(s). Rationale: The estrogen receptors and the estrogens which activate them (including the female hormones estradiol and estrone) are essential for determining female sexual characteristics and help to prevent diseases such as bone loss, heart attack and stroke. After menopause estrogen levels drop by 90% and women become prone to these diseases as well as suffering from other symptoms such as hot flashes. Thus, until recently, and still to a significant extent, many women after menopause began a regime of estrogen supplementation known as hormone replacement therapy (HRT). However, epidemiological data have shown that long-term HRT usage leads to an increased risk of breast and uterine cancers. The projects described in this proposal are aimed at creating safer drugs for HRT. They will also help to understand how cancers develop, particularly breast cancer, and how they can be controlled with the new compounds we are trying to develop.

我的建议包括三个部分，都与药物设计的一般领域有关。 第一部分. 改进药物与蛋白质靶标的结合亲和力的计算。 第二部分. 创造一套完整的雌激素受体激动剂和拮抗剂。 第三部分. 创造一种改进形式的“肽补丁”，以阻止雌激素受体的激活。 基本原理：雌激素受体和激活它们的雌激素（包括雌性激素雌二醇和雌酮）对于决定女性的性特征至关重要，并有助于预防骨质流失，心脏病发作和中风等疾病。 绝经后，雌激素水平下降90%，女性容易患上这些疾病以及其他症状，如潮热。 因此，直到最近，在很大程度上，许多绝经后的妇女开始补充雌激素，称为激素替代疗法（HRT）。 然而，流行病学数据表明，长期使用HRT会导致乳腺癌和子宫癌的风险增加。 本提案中描述的项目旨在为HRT创造更安全的药物。 它们还将有助于了解癌症是如何发展的，特别是乳腺癌，以及如何用我们正在努力开发的新化合物来控制它们。