Design, Synthesis, Biological Activity, and Structural Analysis of Lactam-Constrained PTPRJ Agonist Peptides

ChemMedChem. 2018 Aug 20;13(16):1673-1680. doi: 10.1002/cmdc.201800147. Epub 2018 Jul 4.

Abstract

PTPRJ is a receptor-like protein tyrosine phosphatase mainly known for its antiproliferative and tumor-suppressive functions. PTPRJ dephosphorylates several growth factors and their receptors, negatively regulating cell proliferation and migration. We recently identified a disulfide-bridged nonapeptide, named PTPRJ-19 (H-[Cys-His-His-Asn-Leu-Thr-His-Ala-Cys]-OH), which activates PTPRJ, thereby causing cell growth inhibition and apoptosis of both cancer and endothelial cells. With the aim of replacing the disulfide bridge by a chemically more stable moiety, we have synthesized and tested a series of lactam analogues of PTPRJ-19. This replacement led to analogues with higher activity and greater stability than the parent peptide.

Keywords: cancer; lactam bridge; peptides; phosphatases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Chymotrypsin / chemistry
  • Drug Design
  • Drug Stability
  • Enzyme Activators / chemical synthesis
  • Enzyme Activators / chemistry
  • Enzyme Activators / pharmacology*
  • HeLa Cells
  • Humans
  • Lactams / chemical synthesis
  • Lactams / chemistry
  • Lactams / pharmacology*
  • Molecular Structure
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Proteolysis
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / metabolism
  • Trypsin / chemistry

Substances

  • Antineoplastic Agents
  • Enzyme Activators
  • Lactams
  • Peptides, Cyclic
  • PTPRJ protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3
  • Chymotrypsin
  • Trypsin