Non-proteinogenic amino acids in the pThr-2 position of a pentamer peptide that confer high binding affinity for the polo box domain (PBD) of polo-like kinase 1 (Plk1)

Bioorg Med Chem Lett. 2012 Dec 15;22(24):7306-8. doi: 10.1016/j.bmcl.2012.10.093. Epub 2012 Oct 27.

Abstract

We report herein that incorporating long-chain alkylphenyl-containing non-proteinogenic amino acids in place of His at the pT-2 position of the parent polo-like kinase 1 (Plk1) polo box domain (PBD)-binding pentapeptide, PLHSpT (1a) increases affinity. For certain analogs, approximately two orders-of-magnitude improvement in affinity was observed. Although, none of the new analogs was as potent as our previously described peptide 1b, in which the pT-2 histidine imidazole ring is alkylated at its π nitrogen (N3), our current finding that the isomeric His(N1)-analog (1c) binds with approximately 50-fold less affinity than 1b, indicates the positional importance of attachment to the His imidazole ring. Our demonstration that a range of modified residues at the pT-2 position can enhance binding affinity, should facilitate the development of minimally-sized Plk1 PBD-binding antagonists.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acids / chemistry*
  • Amino Acids / metabolism*
  • Cell Cycle Proteins / chemistry*
  • Cell Cycle Proteins / metabolism*
  • Models, Molecular
  • Peptides / chemistry*
  • Peptides / metabolism*
  • Protein Interaction Domains and Motifs*
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / metabolism*

Substances

  • Amino Acids
  • Cell Cycle Proteins
  • Peptides
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • polo-like kinase 1