Towards mimicking short linear peptide motifs: identification of new mixed α,β-peptidomimetic ligands for SLAM-Associated Protein (SAP) by confocal on-bead screening

M. Hintersteiner, A.J. Knox, G. Mudd, M. Auer

Research output: Contribution to journalArticlepeer-review

Abstract

An array of chemical modifications have recently emerged, designed to improve the stability of natural peptides that inherently suffer from short in vivo half-lives, thereby preventing their use as therapeutics. The resultant peptidomimetics resemble native peptides; however, they contain synthetic elements (e.g. non-coded amino acids) which confer improved biophysical properties. An elegant approach towards the identification of peptidomimetics is through screening of large combinatorial chemical libraries incorporating both coded and non-coded amino acids (e.g. β amino acids). We apply here our recently developed Integrated Chemical Biophysics (ICB) platform, which combines microscale one-bead one-compound screening with fluorescence tagging of retrieved hit beads and subsequent affinity determination of hit compounds in homogenous solution, to the task of identifying novel mixed α, β peptidomimetic binders for the adaptor protein SLAM-associated protein (SAP), which acts as an intracellular adapter that transduces T and NK cell activation. An enhancement to the ICB process is introduced which enables ranking hit compounds from single-point measurements even if the library compound is
Original languageEnglish
Pages (from-to)63-79
Number of pages17
JournalJournal of Chemical Biology
Volume5
Issue number2
DOIs
Publication statusPublished - 1 Jan 2011

Keywords

  • Screening
  • One-bead one-compound
  • SAP
  • Peptidomimetics
  • Docking

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