Our research program aims at developing new chemical and biochemical tools for the understanding and manipulation of cellular processes involving proteins. One project focuses on the development of a general pathway-enabled method for selective protein labeling with small-molecule tags carrying novel chemical functionalities in living cells[1]. In this project, we are engineering the robust ubiquitination pathway, an endogenous biochemical cascade for protein posttranslational modification[2], to carry out site-specific small-molecule labeling of desired proteins for structural and functional studies. In collaboration with Prof. Jian Feng 's group in the Physiology Department, we are designing specific small-molecule inhibitors of ubiquitination enzymes as pharmacological probes for the study of the ubiquitination pathway in neurodegenerative disorders such as Parkinson's disease[3].
The other project involves developing tunable, photoactivated 1,3-dipolar cycloaddition reactions for biological and materials applications. This photoactivated system features a tandem 1,3-dipolar cycloreversion-cycloaddition reaction [4, 5], consisting of an irreversible ring-opening step of substituted tetrazoles upon UV irradiation to yield high-energy nitrilimines dipoles followed by a ring closure step between the 1,3-dipoles and a variety of dipolarophiles such as terminal alkynes, alkenes, and nitriles. The initial work will focus on the mechanistic investigations of the photochemical activation of various tetrazoles compounds and the properties of the resulting nitrilimine intermediates in the subsequent 1,3-cycloaddition reactions including half-life, reactivity, and selectivity. In conjunction with our in vivo protein labeling method, we are exploring using light to enable spatial, temporal manipulation of cellular protein structure and function in vivo.
An integrated approach combining structure-based ligand design, organic synthesis, pathway engineering, and biochemical and cellular models is employed in our investigations. Undergraduate students joining our group will obtain broad training in these areas and make critical contributions to our research objectives.
References
[1] Chen, I.; Ting, A. Y. "Site-specific labeling of proteins with small molecules in live cells" Curr Opin Biotechnol 2005 , 16 , 35 - 40.
[2] Pickart, C. M. "Mechanisms underlying ubiquitination" Annu. Rev. Biochem. 2001 , 70 , 503- 533.
[3] Bossy-Wetzel, E.; Schwarzenbacher, R.; Lipton, S. A. "Molecular pathways to neurodegeneration" Nat Med 2004 , 10 Suppl , S2- 9.
[4] Bianchi, G.; Gandolfi, R. "1,3-Dipolar Cycloreversion" In 1,3-Dipolar Cycloaddition Chemistry ; Padwa, A., Ed.; John Wiley & Sons: New York, 1984; Vol. 2.
[5] Huisgen, R. "1,3-Dipolar cycloadditions" Angew. Chem. Int. Ed. 1963 , 2 , 565 - 598.