title: Membrane permeable cyclic peptidyl inhibitors against human Peptidylprolyl Isomerase Pin1.
abstract: Peptidylprolyl isomerase Pin1 regulates the function and/or stability of phosphoproteins by altering the conformation of specific pSer/pThr-Pro peptide bonds. In this work, a cyclic peptide library was synthesized and screened against the catalytic domain of human Pin1. The selected inhibitors contained a consensus motif of D-pThr-Pip-Nal (where Pip is L-piperidine-2-carboxylic acid and Nal is L-2-naphthylalanine). Representative compounds were tested for binding to Pin1 by isothermal titration calorimetry and inhibition of Pin1 activity, and the most potent inhibitors had K(D) (and K(I)) values in the low nanomolar range. Treatment of breast cancer cells with the inhibitors, which were rendered membrane permeable by attachment of an octaarginine sequence, inhibited cell proliferation and increased the protein levels of two previously established Pin1 substrates, PML and SMRT. Finally, a second generation of cell permeable Pin1 inhibitors was designed by replacing the noncritical residues within the cyclic peptide ring with arginine residues and shown to have antiproliferative activity against the cancer cells.
authors.affiliation: The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Hung-Ying
authors.initials: HY
authors.lastname: Kao
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
mesh_terms: D000595:Amino Acid Sequence; D002151:Calorimetry / Q000379:methods; D002384:Catalysis / Q000187:drug effects; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019151:Peptide Library; D010456:Peptides, Cyclic; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase