CAREER:Yeast-based disulfide trapping for engineering selective inhibitors of a protein kinase
Sheldon Park Principal Investigator
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This NSF award by the Biotechnology, Biochemical and Biomass Engineering program supports work in Prof. Park's lab to engineer and characterize novel peptide inhibitors of the Erk-2 kinase. Erk-2 plays a role in cell development, proliferation, and malignancies, and is an important model system for phosphorylation-dependent signaling in the cell. Considering that the mammalian genome encodes a large number of enzymes involved in phosphorylation regulation, being able to specifically target the activity of select kinases should lead to a better model of intracellular communication as well as to more effective therapeutics against genetic diseases caused by overactive kinases. The proposal seeks to engineer high affinity, high specificity peptide/protein inhibitors of Erk-2 by combining yeast display with disulfide trapping. The designed inhibitors will provide an orthogonal solution to kinase regulation beyond small molecule drugs, and significantly increase the potential pool of candidate molecules for regulating the kinase pathways. The designed peptide inhibitors are expected to have more favorable biophysical properties than small molecule inhibitors, including i) higher specificity of interaction to reduce unwanted side effects, and ii) robustness against fortuitous mutations in the target enzyme to minimize the occurrence of drug resistance. The proposed disulfide trapping strategy, which has been shown to crosslink interacting proteins that are co-expressed in the same yeast cell, provides a unique advantage over conventional screening methods in that the specificity of interaction is intrinsically built in the screen, so that the identified clones are far more likely to be functionally relevant. The successful implementation of the protocol will therefore be highly relevant to other engineering studies of specific protein interactions. <br/>Prof. Park has been an active participant of various outreach programs at UB designed to encourage and retain minority students in science and engineering. The funding will support his continued engagement in educational activities initiated at the university, school and department levels, as well as create venues to initiate other inclusive programs to bring the community and university closer together. Additionally, new pedagogical materials will be developed based on the described research for use in undergraduate chemical and biological engineering classes. The educational components of the proposal will collectively improve the quality of education at multiple levels, while providing scientific stewardship to the public.