Rational design and biological evaluation of cell-permeant small molecule agonists and antagonists of the NAADP receptor

NAADP 受体细胞渗透性小分子激动剂和拮抗剂的合理设计和生物学评价

• 批准号: BB/G009430/2
• 负责人: A Ganesan
• 金额: $ 13.4万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG009430%2F2
• 关键词: Rational; design; biological; evaluation; cell

Cells can be thought of as minature factories, with protein machines (enzymes) performing the work and chemical messengers instructing the machines to start, stop, faster slower. The protein machines are built from instructions written in DNA. So, now that the entire humane genome is known, we know the structure of all the machines, but we understand far less about how the machines operate together. A very powerful way to investigate this problem is to use small molecule chemical tools that mimic the natural chemical messengers. Chemical messengers are produced within a cell and generally do not leak out; small molecule chemical tools can pass in and out of cells easily, so they can be applied to cells, tissues or, in the case of drugs, swallowed as tablets. It is desireable to have chemical tools that modulate the activity of the enzymes such that they inhibit (antagonists) or stimulate (agonists). NAADP is a chemical messenger for which we know little. We previously used computers to screen millions of chemicals to find ones that might affect the proteins responsive to NAADP. We found a compound, Ned-14, that antagonizes NAADP's action. We now want to modify the chemcial structure of Ned-14: (1) to obtain a better antagonist; (2) to find an agonist; and (3) to find antagonists and agonists that are selective for, say, pancreas, heart or neurons. These chemical tools will enable us and our colleagues to learn more about the roles played by NAADP in biology. For example, Ned-14 already has revealed a role for NAADP in the molecular steps linking glucose sensing to insulin release. Not only does this reveal new biology, but might, ultimately, lead to the ideantification of new drug targets and drug-based therapies.

细胞可以被认为是微型工厂，蛋白质机器（酶）执行工作，化学信使指示机器启动，停止，更快更慢。蛋白质机器是根据DNA中的指令构建的。所以，现在人类的基因组已经被知道了，我们知道了所有机器的结构，但我们对机器如何协同工作的了解要少得多。研究这个问题的一个非常有效的方法是使用模拟天然化学信使的小分子化学工具。化学信使在细胞内产生，通常不会泄漏;小分子化学工具可以很容易地进出细胞，因此它们可以应用于细胞，组织，或者在药物的情况下，作为片剂吞咽。期望具有调节酶活性的化学工具，使得它们抑制（拮抗剂）或刺激（激动剂）。NAADP是一种化学信使，我们对此知之甚少。我们之前使用计算机筛选了数百万种化学物质，以找到可能影响NAADP反应蛋白质的化学物质。我们发现了一种化合物Ned-14，可以对抗NAADP的作用。我们现在想要修改Ned-14的化学结构：（1）获得更好的拮抗剂;（2）寻找激动剂;（3）寻找对胰腺、心脏或神经元等有选择性的拮抗剂和激动剂。这些化学工具将使我们和我们的同事能够更多地了解NAADP在生物学中所扮演的角色。例如，Ned-14已经揭示了NAADP在连接葡萄糖传感和胰岛素释放的分子步骤中的作用。这不仅揭示了新的生物学，而且可能最终导致新的药物靶点和基于药物的疗法的识别。