Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12

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On the basis of computational design, a focused one-bead one-compound library has been prepared on microparticle-encoded PEGA1900 beads consisting of small tripeptides with a triazole-capped N-terminal. The library was screened towards a double point-mutated version of the human FKBP12 protein, known as the destabilizing domain (DD). Inspired by the decoded library hits, unnatural peptide structures were screened in a novel on-bead assay, which was useful for a rapid structure evaluation prior to off-bead resynthesis. Subsequently, a series of 19 compounds were prepared and tested using a competitive fluorescence polarization assay, which led to the discovery of peptide ligands with low micromolar binding affinity towards the DD. The methodology represents a rapid approach for identification of a novel structure scaffold, where the screening and initial structure refinement was accomplished using small quantities of library building blocks.

Original languageEnglish
JournalACS Combinatorial Science
Issue number3
Pages (from-to)156-164
Publication statusPublished - 2020

    Research areas

  • destabilizing domain, encoded beads, one-bead one-compound library, solid-phase synthesis

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ID: 237843368