Design, synthesis, and bioactivities of tasiamide B derivatives as cathepsin D inhibitors

J Pept Sci. 2019 Apr;25(4):e3154. doi: 10.1002/psc.3154. Epub 2019 Feb 7.

Abstract

Cathepsin D (Cath D) is overexpressed and hypersecreted by malignant tumors and involved in the progress of tumor invasion, proliferation, metastasis, and apoptosis. Cath D has been considered as a potential target to treat cancer. Our previous studies revealed that tasiamide B derivatives TB-9 and TB-11 exhibited high potent inhibition against Cath D and other aspartic proteases, but their molecular weights are still high, and the role of each residue is unknown yet. Based on this, two series of tasiamide B derivatives have been designed, synthesized, and evaluated for their inhibitory activity against Cath D/Cath E/BACE1. Enzymatic assays revealed that the target compound 1 with lower molecule weight showed good inhibitory activity against Cath D with IC50 of 3.29 nM and satisfactory selectivity over Cath E (72-fold) and BACE1 (295-fold), which could be a valuable template for the design of highly potent and selective Cath D inhibitors.

Keywords: Ahppa; cathepsin D; selective inhibitor; tasiamide B derivatives.

MeSH terms

  • Cathepsin D / antagonists & inhibitors*
  • Cathepsin D / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Molecular Structure
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Oligopeptides
  • Protease Inhibitors
  • tasiamide B
  • Cathepsin D