co9b00197_si_001.pdf (6.07 MB)
Design and Combinatorial Development of Shield‑1 Peptide Mimetics Binding to Destabilized FKBP12
journal contribution
posted on 2020-02-23, 13:13 authored by Daniel Madsen, Frederik P. Jørgensen, Daniel Palmer, Milena E. Roux, Jakob V. Olsen, Mikael Bols, Sanne Schoffelen, Frederik Diness, Morten MeldalOn
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.
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peptide structuresfluorescence polarization assayDDmicromolar binding affinitynovel structure scaffoldoff-bead resynthesisnovel on-bead assayDestabilized FKBP 12one-bead one-compound librarypoint-mutated versiondecoded library hitsstructure refinementCombinatorial Developmenttriazole-capped N19 compoundspeptide ligandsmicroparticle-encoded PEGA 1900 beadsFKBP 12 proteinlibrary building blocksstructure evaluation
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