Chemical-genetic approaches

The application of forward chemical genetics to studies of translation provides an opportunity to identify small molecules that inhibit or stimulate this process without any underlying assumptions as to which step is most amenable to targeting by the chemical libraries under consideration. The opportunity exists to identify novel factors involved in translation, unravel new activities of known translation initiation factors, or characterize shortlived intermediates that are frozen by the small molecule inhibitor. We have undertaken a forward chemical genetic approach to identify small molecules that inhibit or stimulate translation in extracts prepared from Krebs-2 ascites cells (Novae et al., 2004). These screens have led to the identification of several novel inhibitors of translation initiation and elongation (Bordeleau et al., 2005, 2006 Robert et al., 2006a,b). 

Watashi K, Shimotohno K. (2007) Chemical genetics approach to hepatitis C virus replication Cyclophilin as a target for anti-hepatitis C virus strategy. Rev Med Virol 17 245-252. 

It is critical to this chemical genetic approach to have a library of compounds that have a high probability of being relatively selective otherwise, the ability to interpret the results becomes at least as complex as deciphering highly poly-genetic phenotypes. To address this, diversity-oriented synthesis has been proposed to provide arrays of complex small molecules that are easily synthesized. The natural-product basis for many of the molecules and their complexity are believed to contribute to their cellular potency and selectivity (6). This chemical genetic approach has been applied to identify novel inhibitors of alpha-tubulin and histone deactylation (7). 

As in classical genetics, a chemical genetic approach involves screening with probes that potentially could interact with any target in the genome, while trying to identify specific phenotypes. An alternate approach, termed reverse chemical... 

Fig. 1. Comparison of genetic and chemical genetics. In the traditional genetics approach genes are mutated resulting in missing or altered protein products. In a chemical genetic approach, compounds bind to specific proteins modulating their normal physiological functions. The throughput at steps A, B, C is used in Table 1 to help define the different chemical genetic approaches.

The different chemical genetic approaches described in the above subheadings are summarized in Table 1. 

Chen X, Ye H, Kuruvilla R, et al. A chemical-genetic approach to studying neurotrophin signaling. Neuron 2005 46(1) 13-21. 

This work elegantly demonstrates power of combined ABPP and chemical genetics approaches in understanding microbial pathogenesis, and has made a very real contribution to the identification of potential novel dmg targets. 

Chemical genetics approaches provide some assistance in pursuing this path. 

P. J. Alaimo, M. A. Shogren-Knaak, and K. M. Shokat, Chemical genetic approaches for the elucidation of signaling pathways, Curr. Opin. Chem. Biol. 5 (2001), 360-367. 

Blackwell FIE, Zhao YD. Chemical genetic approaches to plant biology. Plant Physiol. 2003 133 448-455. 

Shokat K, Velleca M. Novel chemical genetic approaches to the discovery of signal transduction inhibitors.(see comment). Drug Discov. Today 2002 7 872-879. 

Chan J, Bayliss PE, Wood JM, Roberts TM. Dissection of angiogenic signaling in zebrafish nsing a chemical genetic approach. Cancer CeU 2002 1 257-267. 

In addition to biological and retroactive approaches to molecular target definition, one can also return to classical approaches of cell metabolism and biochemistry. Since these suggest single targets, they can be inefficient. Chemical genetics approaches have recently been explored with libraries of molecules and precisely defined organisms. 

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