Small molecule keys (SMK) for functional assignments in post-translational protein modification

人类基因组是对构成基因的最初DNA序列进行编目的，它只是新科学领域的一个起点，新科学领域将利用人类基因组中几乎未开发的数据。利用这一基因组数据的一个主要瓶颈是在分子、细胞和生理水平上分配基因产物的功能。最近的发展，包括“转基因”和“RNA干扰”（RNAi）技术直接干扰DNA编码或编码被“读取”的过程。这些都使得进步，以越来越快的速度，但是，他们遭受重大的限制，如在生物体内交付的困难和不完善的控制其效果的时间。此外，这些变化往往太“远”（在相关的生物学途径方面），从研究中的生化事件，因此，效果或获得的信息，那么不太清楚。几十年来，小分子已被证明是生物系统中的宝贵工具。现在存在用于小分子的逻辑设计的集合（所谓的“聚焦库”）的有效化学合成和分析的方法。使用这种化学合成方法，我们将尝试产生细胞穿透分子，旨在选择性地改变蛋白质靶点的过程。选择这些小分子键（SMK）以靶向家族或相关蛋白质的每个成员。使用这些化学“钥匙”，我们“解锁或锁定”它们的功能和家族的功能，从而检查和利用由此产生的影响。我们最初的目标蛋白是具有挑战性和令人兴奋的。这些蛋白质参与了所谓的翻译后修饰（PTM）-在基因编码构建后对蛋白质结构进行的改变。由于这些过程不受直接的遗传控制，它们的研究到目前为止一直很困难-我们所知道的很少，表明PTM对生物过程的影响可能是深远的。我们的目标是看到SMK中心的第一阶段有多深刻-我们的目标是创建一个网站，作为一个地方，国家和国际资源，以合作的方式为广泛的生物过程生成和应用小分子。

The human genome, which catalogues the initial DNA sequences that go to make up genes, is just a starting point in new realms of science that will make use of the virtually untapped data that lies within. A major bottleneck in the exploitation of this genomic data is the assignment of function for gene products, at the molecular, cellular and physiological levels. Recent developments, including 'transgenic' and 'RNAinterference' (RNAi) technologies directly interfere with the DNA coding or the processes by which the coding is 'read'. These have enabled advances to be made at an increasing pace, however, they suffer from significant limitations, such as difficulties of delivery inside organisms and imperfect control of the timing of their effect. In addition, these changes are often too 'far' (in terms of relating biological pathways) from the biochemical event under study and so the effect or information gained is then less clear. For many decades, small molecules have proven to be invaluable tools in biological systems. Methodology now exists for the efficient chemical synthesis and analysis of logically-designed collections (so-called 'focused libraries') of small molecules. Using this chemical synthetic methodology we will attempt to generate cell-penetrating molecules designed to selectively change the process of protein targets. These small molecule keys (SMKs) are chosen to target for each member of a family or related proteins. Using these chemical 'keys' we 'unlock or lock' their function and that of the family and so examine and exploit the resulting effects. Our initial target proteins are challenging and exciting ones. These are proteins involved in so-called post-translational modifications (PTMs) - changes that are made to protein structures after their genetically-encoded construction. Since these processes are not under direct genetic control, their study has until now been difficult - the little we do know shows that the effect of PTMs on biological processes can be profound. We aim to see just how profound in the first stage of the SMK centre - a site that we aim to create to act as a local, national and international resource for the generation and application of small molecules for a wide range of biological processes in a cooperative manner.