NUS: Department of Chemistry

Elucidating the function of every gene from the sequence data of tens of thousands of genes (so called functional genomics) is the next major step for the human genome project. Geneticists have conventionally investigated the function of unknown genes by comparing the normal phenotype with that of knock-outs or through the over-expression of target genes. A novel approach utilizing chemical library screening to find an interesting phenotypic change by targeting the specific gene product, a protein, has emerged as an alternative tactic- so called chemical genetics. In chemical genetics, one chemical compound may specifically inhibit or activate one (or multiple) target proteins. Therefore, the compound is equivalent to a gene knock-out or the over-expression of the gene in conventional genetics.

Although the current chemical genetics approach is very attractive, it contains intrinsically difficult steps.The biggest hurdle is the modification step of the lead compound into the affinity molecule (Figure 1-c).In order to add a linker to the lead compound without activity loss, a thorough SAR (structure-activity relationships) study is required to find the proper site of linker addition (most likely a site of the lead compound exposed to the solvent from the binding pocket of the target protein). To avoid this well-known problem, our approach is employing library molecules carrying a Tag (TL: Tagged Library) from the beginning.

In addition to biological activity and target identification, the localization of molecules in living systems will provide greater insights into the molecular mode of action. Popularly, fluorescent labeling of the active molecules has been used. While the linker tag could easily be used to attach the active compound to a fluorescence moiety, the size of the fluorophore, as large as or larger than the active molecule itself, can completely alter the chemical/physical properties of the original active compounds. To avoid this problem, an intrinsically tagged library approach has been developed and demonstrated as Amyloid plaque detection in Alzheimer disease brain (Fig 2).

Currently, this strategy can be used to associate one molecule with the organelle or cellular location in which its target is located. Eventually, the exact protein(s) target for each localizing compound will be determined, which will open up the possibility for truly high throughput chemical genomics or proteomics. Further advancements will allow the relevant fluorescent compound to be used as a molecular probe for desired cellular components. Phenotypic screening of this tagged library will offer a high throughput screening method for colorful chemical genomics. Altering the included tag will offer even greater experimental possibilities.

Organic dyes, which change color in response to analyte(s), have been used as optical/visual sensors for more than hundred years. In most cases, the main issue is selectivity of the sensor only toward the target analyte, which is highly challenging to achieve. Our taste/smell sensory organs (tongue and nose) are known to have from dozens to hundreds of receptors, but they can differentiate and identify tens of thousands of different tastes and smells by analyzing the unique patterns generated by each receptor's response. It is noteworthy that in this pattern analysis, each individual receptor does not need to be specific or selective to a given analyte for identification. Inspired by this Mother Nature's combinatorial sensing approach, many artificial sensory systems using multiple probes or sensor arrays based on optical measurements have been developed. So far, our artificial tongue has been demonstrated 47 cation and 23 carbohydrate discrimination successfully. The future research will focus on clinical samples for diagnosis and medicinal purpose.

Representative Publications

1. Colorimetric identification of carbohydrates by a pH indicator/ pH change inducer ensemble, Lee, J. W.; Lee, J. S.; Chang, Y. T.* Angew. Chem., Int. Ed. Engl., 2006, 45, 6485-6487. Highlighted at "Discriminating between carbohydrates, C&En News, 2006 (September 25), 84 (39), p 90"

2. Forward chemical genetic approach identifies new role for GAPDH in insulin signaling, Min, J. K.; Kim, Y. K.; Cipriani, P. G.; Kang, M.; Khersonsky, S. M.; Walsh, D. P.; Lee, J. Y.; Niessen, S.; Yates, J. R.; Gunsalus, K.; Piano, F.; Chang, Y. T.* Nat. Chem. Biol. 2007, 3, 55-59. Highlighted at "New diabetes target, C&En News, 2006 (December 4), 84 (49), p 63" & "NYU, Scripps Finding Offers New Path For Treatment Of Diabetes, Medical News Today, 2006 (November 30)"

3. Facilitated forward chemical genetics using tagged library, Ahn, Y. H.; Chang, Y. T.* Acc. Chem. Res. 2007, 40, 1025-1033

4. Discovery of heparin chemosensors through diversity oriented fluorescence library approach, Wang, S.; Chang, Y. T.* Chem. Commun. 2008, 1173-1175. Highlighted at "Blood sensor for safer surgery, Chemical Biology (RSC), 2008 (January 10)"

5. Small-molecule fluorophores to detect cell-state switching in the context of high-throughput screening, Wagner, B. K.; Carrinski, H. A.; Ahn, Y. H.; Kim, Y. K.; Gilbert, T. J.; Fomina, D. A.; Schreiber, S. L.; Chang, Y. T.; Clemons, P. A. J. Am. Chem. Soc. 2008, 130, 4208-4209.

6. Diversity oriented fluorescence library approach (DOFLA) to the discovery of chymotrypsin sensor, Wang, S.; Kim, Y. K.; Chang, Y. T.* J. Comb. Chem. 2008, 10, 460-465.

7. Forward chemical genetics, Chang, Y. T.* in “Wiley Encyclopedia of Chemical Biology”, vol 2, pp94-111, Ed. Tadhq P. Beqley, Hoboken, N.J: John Wiley & Sons, 2009.

8. Diversity-Oriented Fluorescence Library Approach for Discovery of Sensors and Probe, Lee, J. S.; Kim, Y. K.; Vendrell, M.; Chang, Y. T.* Mol. Biosyst. 2009, 5, 411-421.

9. Synthesis of a bodipy library and its application to the development of live cell glucagon imaging probe, Lee, J. S.; Kang, N. Y.; Kim, Y. K.; Samanta, A.; Feng, S.; Kim, H. K.; Vendrell, M.; Park, J. H.; Chang, Y. T.* J. Am. Chem. Soc. 2009, 131, 10077-10082.

Associate Professor CHANG YOUNG-TAE

Research Interests

Representative Publications