Structure-Activity Relationship in Pyrazolo[4,3- c]pyridines, First Inhibitors of PEX14-PEX5 Protein-Protein Interaction with Trypanocidal Activity

J Med Chem. 2020 Jan 23;63(2):847-879. doi: 10.1021/acs.jmedchem.9b01876. Epub 2020 Jan 6.


Trypanosoma protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against Trypanosoma is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 PPI. The optimization was driven by several X-ray structures, NMR binding data, and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against Trypanosoma, including the human pathogen Trypanosoma brucei gambiense and Trypanosoma cruzi parasites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Magnetic Resonance Spectroscopy
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / biosynthesis
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Myoblasts / drug effects
  • Myoblasts / parasitology
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / biosynthesis
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Trypanocidal Agents / chemical synthesis*
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei gambiense / drug effects
  • Trypanosoma brucei gambiense / metabolism
  • Trypanosoma brucei rhodesiense / drug effects


  • Membrane Proteins
  • PEX14 protein, Trypanosoma brucei
  • Protozoan Proteins
  • Pyridines
  • Trypanocidal Agents