Poster abstracts

Poster number 65 submitted by Tao Liu

Identification of Potent Cyclic Peptidyl Pin1 Inhibitors from a Combinatorial Library

Tao Liu (The Ohio State Biochemistry Program, the Ohio State University), Yu Liu (Department of Biochemistry, Case Western Reserve University), Hung-Ying Kao (Department of Biochemistry, Case Western Reserve University), Dehua Pei (Department of Chemistry, the Ohio State University)

Abstract:
Pin1 is a peptidyl-prolyl isomerase which plays a significant role in cell-cycle regulation by altering the conformation, thus the function/stability of targeted phosphoproteins. Recent studies have suggested Pin1 as a potential target for anticancer drug design. A D-phosphoserine and D-phosphothreonine containing head-to-tail cyclic peptide library was built based on Pin1 structure and substrate specificity. After screening the library against Pin1, a few peptides were selected, individually synthesized and test for binding. The peptides were shown to bind to Pin1 with a Kd ranging from 20nM - 1.6uM by isothermal titration calorimetry. The inhibition potency was confirmed by in vitro enzymatic assays. To test whether Pin1 inhibitor is active in the cells, we examined the effects of one of the Pin1 inhibitor on the protein levels of two known Pin1 targets, PML and SMRT. Our data show that treatment of HeLa cells with the Pin1 inhibitor leads to increases in the protein levels of PML and SMRT.

Keywords: Pin1 inhibitor, cyclic peptides, combinatorial chemistry