Chemical Modification of Phage-Displayed Helix-Loop-Helix Peptides to Construct Kinase-Focused Libraries

Chembiochem. 2021 Dec 10;22(24):3406-3409. doi: 10.1002/cbic.202100450. Epub 2021 Oct 19.

Abstract

Conformationally constrained peptides hold promise as molecular tools in chemical biology and as a new modality in drug discovery. The construction and screening of a target-focused library could be a promising approach for the generation of de novo ligands or inhibitors against target proteins. Here, we have prepared a protein kinase-focused library by chemically modifying helix-loop-helix (HLH) peptides displayed on phage and subsequently tethered to adenosine. The library was screened against aurora kinase A (AurA). The selected HLH peptide Bip-3 retained the α-helical structure and bound to AurA with a KD value of 13.7 μM. Bip-3 and the adenosine-tethered peptide Bip-3-Adc provided IC50 values of 103 μM and 7.7 μM, respectively, suggesting that Bip-3-Adc bivalently inhibited AurA. In addition, the selectivity of Bip-3-Adc to several protein kinases was tested, and was highest against AurA. These results demonstrate that chemical modification can enable the construction of a kinase-focused library of phage-displayed HLH peptides.

Keywords: bivalent inhibitors; modality; peptide library; phage display; protein kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase A / metabolism*
  • Humans
  • Peptide Library
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*

Substances

  • Peptide Library
  • Peptides
  • Protein Kinase Inhibitors
  • AURKA protein, human
  • Aurora Kinase A

Grants and funding