Novel DOCK2-selective inhibitory peptide that suppresses B-cell line migration

Biochem Biophys Res Commun. 2017 Jan 29;483(1):183-190. doi: 10.1016/j.bbrc.2016.12.170. Epub 2016 Dec 27.

Abstract

Dedicator of cytokinesis 2 (DOCK2) is a key molecule for lymphocyte activation and migration. DOCK2 interacts with Ras-related C3 botulinus toxin substrate 1 (Rac1, GTPase) and mediates the GDP-GTP exchange reaction, indicating that inhibitors against protein-protein interaction (PPI) between DOCK2 and Rac1 would be good drug candidates for treating immune-related disorders. Here, we report DOCK2-selective PPI inhibitory peptides discovered using random peptide T7 phage display technology. These peptides inhibited DOCK2 activity at nanomolar concentrations and were delivered to intracellular compartments by combination with cell-penetrating peptide (CPP). Consequently, one peptide, R4-DCpep-2(V2W/K4R/ox)-NH2 (Ac-RRRRCWARYHGYPWCRRRR-NH2), inhibited migration in human B lymphocyte MINO cell line at IC50 = 120 nM. To our knowledge, this is the first report of a DOCK2-selective peptide inhibitor; this study will contribute to the development of novel DOCK2-targeting immunosuppressive drugs.

Keywords: CPP; Cell migration; DOCK2; PPI; Peptide; Phage display.

MeSH terms

  • Cell Line, Tumor / drug effects
  • Cell Movement / drug effects
  • Cell-Free System
  • Drug Evaluation, Preclinical / methods
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors*
  • Humans
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / pathology
  • Peptide Library
  • Peptides / chemistry*
  • Peptides / metabolism
  • Peptides / pharmacology*
  • Protein Interaction Maps
  • rac1 GTP-Binding Protein / metabolism

Substances

  • DOCK2 protein, human
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors
  • Peptide Library
  • Peptides
  • RAC1 protein, human
  • rac1 GTP-Binding Protein