Facile Synthesis of Dimeric Thioether-Macrocyclic Peptides with Antibody-like Affinity against Plexin-B1

Bioconjug Chem. 2018 Jun 20;29(6):1847-1851. doi: 10.1021/acs.bioconjchem.8b00219. Epub 2018 May 21.

Abstract

Macrocyclic peptides have gained increasing attention due to their ease of discovery through various in vitro display platforms as well as their potential in possessing favorable properties of both small molecule and antibody drug classes. It is well-known that the avidity achieved through the bivalent binding mode of antibodies gives rise to their slow dissociation rates and thus high potency as drug molecules. Here, we report the synthesis of dimeric thioether-macrocyclic peptides through a branched synthesis approach allowing for synthesis of dimeric peptides in a comparable number of steps as monomers and tunability of linker lengths from 30 to 200 Å. Applying this method to synthesize dimers of a model PlexinB1-binding macrocyclic peptide showed close to 300-fold increases in their apparent binding affinity, bringing the KD down from 8 nM to 30 pM as well as affording improved biological activities when compared to their monomeric counterparts. These enhancements demonstrate that this is a simple synthetic strategy to harness the benefits of bivalence that antibodies naturally possess.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / chemistry
  • Antibodies / pharmacology
  • Humans
  • Macrocyclic Compounds / chemical synthesis*
  • Macrocyclic Compounds / chemistry
  • Macrocyclic Compounds / pharmacology*
  • Molecular Docking Simulation
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / metabolism*
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Protein Binding
  • Protein Interaction Maps / drug effects
  • Protein Multimerization
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / metabolism*
  • Sulfides / chemical synthesis
  • Sulfides / chemistry
  • Sulfides / pharmacology

Substances

  • Antibodies
  • Macrocyclic Compounds
  • Nerve Tissue Proteins
  • PLXNB1 protein, human
  • Peptides, Cyclic
  • Receptors, Cell Surface
  • Sulfides