Florian Stefan, Hümmer Stefan, Catarinella Mario, Mayer Thomas U
Chemical Genetics, Independent Research Group, Department of Cell Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18, 82152, Martinsried, Germany.
HFSP J. 2007 Jul;1(2):104-14. doi: 10.2976/1.2752600. Epub 2007 Jul 12.
To understand biological processes, biologists typically study how perturbations of protein functions affect the phenotype. Protein activity in living cells can be influenced in many different ways: by manipulation of the genomic information, by injecting inhibitory antibodies, or, more recently, by the use of ribonucleic acid-medicated interference (RNAi). All these methods have proven to be extremely helpful, as they possess a high degree of specificity. However, they are less suitable for experiments requiring precise timing and fast reversibility of the perturbation. The advantage of small molecules is that they specifically interact with their target on a fast time scale and often in a reversible manner. In the last 15 years, this approach, termed "chemical genetics," has received a lot of attention. The term genetics pays tribute to the analogy between chemical genetics and the classic genetic approach, where manipulations at the gene level are used to draw conclusions about the function of the corresponding protein. Chemical genetics has only recently been used as a systematic approach in biology. The term was coined in the 1990's, when combinatorial chemistry was developed as a fast method to synthesize large compound libraries [Mitchison (1994) "Towards a pharmacological genetics," Chem. Biol. 1, 3-6; Schreiber (1998) "Chemical genetics resulting from a passion for synthetic organic chemistry," Bioorg. Med. Chem. 6, 1127-1152].
为了理解生物过程，生物学家通常研究蛋白质功能的扰动如何影响表型。活细胞中的蛋白质活性可以通过多种不同方式受到影响：通过操纵基因组信息、注射抑制性抗体，或者最近通过使用核糖核酸介导的干扰（RNAi）。所有这些方法都已被证明非常有用，因为它们具有高度的特异性。然而，它们不太适合需要精确计时和扰动快速可逆性的实验。小分子的优势在于它们能在快速的时间尺度上特异性地与靶点相互作用，而且通常是以可逆的方式。在过去15年里，这种被称为“化学遗传学”的方法受到了广泛关注。“遗传学”这个术语体现了化学遗传学与经典遗传学方法之间的类比，在经典遗传学方法中，基因水平的操作被用来推断相应蛋白质的功能。化学遗传学直到最近才在生物学中被用作一种系统方法。这个术语是在20世纪90年代创造的，当时组合化学作为一种合成大型化合物库的快速方法得到了发展[米奇森（1994年）“走向药理遗传学”，《化学生物学》1，3 - 6；施赖伯（1998年）“源于对合成有机化学的热爱的化学遗传学”，《生物有机与药物化学》6，1127 - 1152]。
