title: Isolation and characterization of coactivator-binding peptoids from a combinatorial library.
abstract: Pharmacologic agents capable of activating the expression of specific genes would be valuable tools in biological research and could potentially be useful therapeutically. Efforts to develop a general solution to this problem have focused on the discovery of cell permeable mimics of native transcription factors comprised of linked DNA-binding and activation domain surrogates. Recently, we reported the isolation of a peptoid, called KBPo2, that binds a fragment of the mammalian coactivator CREB-binding protein (CBP). When delivered to a promoter-bound DNA-binding domain, this peptoid acted as a potent activation domain mimic in human cells. In this paper, we provide full details of the screening experiments and also report further characterization of this molecule as well as the other peptoids that came out of the screen. Of the three peptoids identified as putative CBP ligands, only KBPo2 demonstrated the necessary combination of binding affinity, specificity and cell permeability necessary to function as a potent activation domain mimic in cells. KBPo2 binds to CBP in a region different than that recognized by the native activation peptide from the transcription factor CREB.
authors.affiliation: Division of Translational Research, Department of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9185, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Alluri
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Xiao
authors.forename: Thomas
authors.initials: T
authors.lastname: Kodadek
mesh_terms: D050882:CREB-Binding Protein / Q000378:metabolism*; D002463:Cell Membrane Permeability; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D019151:Peptide Library; D034444:Peptoids / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D019151:Peptide Library; D034444:Peptoids; D050882:CREB-Binding Protein; C494363:CREBBP protein, human