Selective Recognition of Folded RNA by Small Oligomers

小寡聚体选择性识别折叠 RNA

• 批准号: 7152077
• 负责人: daniel appella
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 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/7152077
• 关键词: RNA; active sites; chemical binding; drug design /synthesis /production; human immunodeficiency virus; polyamines; small molecule; virus RNA

The protein p53 is recognized as one of the most important guardians in the body that prevents tumor development. Since its discovery, the roles of p53 have been the focus of research geared toward understanding the mechanisms of uncontrolled cell growth or cancer. Specifically, when healthy cells are damaged, p53 levels increase, followed by inhibition of cell growth or programmed cell death. This regulation of damaged cells is initiated by a p53-DNA binding event. Mutated forms of p53 that lose the ability to bind DNA can not arrest cell growth, and the proliferation of damaged cells results. Mutant forms of p53 are present in approximately 50% of all human cancers. If mutant p53 can be induced to readopt the active form of wild-type p53, tumor suppressor function can be restored. Molecules that reactivate mutant p53 could selectively target tumor cells due to the accumulation of mutated p53 in these cells. In our research, we are developing a unique class of molecules to reactivate mutant p53 associated with cancer. We have developed a synthetically accessible class of molecules that can be easily modified to examine structural activity relationships, mechanism of biological activity, or optimize for anticancer activity, and we are currently examining the activity of these molecules in a variety of cancer cell lines.

p53蛋白被认为是体内防止肿瘤发展的最重要的守护者之一。自发现以来，p53的作用一直是研究的焦点，旨在了解不受控制的细胞生长或癌症的机制。具体来说，当健康细胞受损时，p53水平升高，随后是细胞生长抑制或程序性细胞死亡。这种对受损细胞的调节是由p53-DNA结合事件启动的。失去结合DNA能力的突变形式的p53不能阻止细胞生长，结果是受损细胞的增殖。p53的突变形式存在于大约50%的人类癌症中。如果可以诱导突变型p53重新采用野生型p53的活性形式，则可以恢复肿瘤抑制功能。由于突变p53在肿瘤细胞中积累，重新激活突变p53的分子可以选择性地靶向肿瘤细胞。在我们的研究中，我们正在开发一种独特的分子来重新激活与癌症相关的p53突变体。我们已经开发了一种可合成的分子，可以很容易地修改来检查结构活性关系，生物活性机制，或优化抗癌活性，我们目前正在检查这些分子在各种癌细胞系中的活性。