Bacterially Secretable Single-Chain Tandem Macrocyclic Peptides for High Affinity and Inhibitory Activity

Chembiochem. 2023 Jan 17;24(2):e202200599. doi: 10.1002/cbic.202200599. Epub 2022 Dec 7.

Abstract

The inhibition of protein-protein interactions (PPIs) is an effective approach for therapy. Owing to their large binding surface areas to target proteins, macrocyclic peptides are suitable molecules for PPI inhibition. In this study, we developed single-chain tandem macrocyclic peptides (STaMPtides) that inhibits the vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2). They were artificially designed to comprise two different VEGFR2-binding macrocyclic peptides linked in tandem by peptide linkers and secreted by Corynebacterium glutamicum. Most potent VEGFR2-inhibitory STaMPtides with length-optimized linkers exhibited >1000 times stronger inhibitory activity than their parental monomeric peptides, possibly due to the avidity effect of heterodimerization. Our approach of using STaMPtides for PPI inhibition may be used to inhibit other extracellular factors, such as growth factors and cytokines.

Keywords: avidity; dimerization; macrocyclic peptides; microbial secretion; protein-protein interactions.

MeSH terms

  • Intercellular Signaling Peptides and Proteins
  • Peptides* / chemistry
  • Vascular Endothelial Growth Factor A*

Substances

  • Vascular Endothelial Growth Factor A
  • Peptides
  • Intercellular Signaling Peptides and Proteins