Solvent-Free procedure of an A9 Peptide Dimer Exhibiting Specific HER2 Receptor Binding: Fluorescence Spectroscopy Evaluation of the Enhanced Binding Affinity

J Med Chem. 2025 Aug 14;68(15):16299-16305. doi: 10.1021/acs.jmedchem.5c01194. Epub 2025 Jul 24.

Abstract

HER2-expressing cancers currently benefit from targeted therapies, including monoclonal antibodies and antibody-drug conjugates that specifically bind to the extracellular domain of the receptor. Peptides targeting HER2 represent promising candidates for the development of alternative molecular drugs. In this study, we report a dimeric version of the previously validated A9 peptide as a ligand specifically targeting HER2. The novel A9-PEG-A9 conjugate consists of two A9 peptides whose N-terminal amino groups are linked via a polyethylene glycol chain. It was synthesized using a solvent-free protocol and validated as an improved ligand, demonstrating enhanced water solubility and increased affinity for the model receptor HER2-DIVMP, as determined by the fluorescence spectroscopy titration method.

MeSH terms

  • Dimerization
  • Erb-b2 Receptor Tyrosine Kinases* / chemistry
  • Erb-b2 Receptor Tyrosine Kinases* / metabolism
  • Humans
  • Ligands
  • Peptides* / chemical synthesis
  • Peptides* / chemistry
  • Peptides* / metabolism
  • Polyethylene Glycols / chemistry
  • Protein Binding
  • Solvents
  • Spectrometry, Fluorescence

Substances

  • Erb-b2 Receptor Tyrosine Kinases
  • Peptides
  • Polyethylene Glycols
  • Ligands
  • Solvents
  • ERBB2 protein, human