A fragment-based selection approach for the discovery of peptide macrocycles targeting protein kinases

Elizabeth Restituyo, Karla Camacho-Soto, Indraneel Ghosh

Research output: Contribution to journalArticle

Abstract

Protein kinases are implicated in diverse signaling cascades and have been targeted with small molecules that typically bind the conserved ATP-binding active site. These inhibitors are often promiscuous and target multiple protein kinases, which has led to the development of alternate strategies to discover selective ligands. We have recently described a fragment-based selection approach, where a small-molecule warhead can be non-covalently tethered to a phage-displayed library of cyclic peptides. This approach led to the conversion of the promiscuous kinase inhibitor, staurosporine, into a selective bivalent inhibitor.

Original languageEnglish (US)
Pages (from-to)95-104
Number of pages10
JournalMethods in molecular biology (Clifton, N.J.)
Volume1248
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Protein Kinases
Cyclic Peptides
Peptides
Staurosporine
Bacteriophages
Catalytic Domain
Phosphotransferases
Adenosine Triphosphate
Binding Sites
Ligands

Keywords

  • Allosteric inhibitors
  • Bivalent inhibitors
  • Fragment-based ligand discovery
  • Peptide macrocycles
  • Phage display
  • Protein kinases
  • Solid-phase peptide synthesis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

Cite this

A fragment-based selection approach for the discovery of peptide macrocycles targeting protein kinases. / Restituyo, Elizabeth; Camacho-Soto, Karla; Ghosh, Indraneel.

In: Methods in molecular biology (Clifton, N.J.), Vol. 1248, 2015, p. 95-104.

Research output: Contribution to journalArticle

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