Inhibition of Human Cathepsins B and L by Caffeic Acid and Its Derivatives

Biomolecules. 2020 Dec 29;11(1):31. doi: 10.3390/biom11010031.


Caffeic acid (CA) and its derivatives caffeic acid phenethyl ester (CAPE) and chlorogenic acid (CGA) are phenolic compounds of plant origin with a wide range of biological activities. Here, we identify and characterize their inhibitory properties against human cathepsins B and L, potent, ubiquitously expressed cysteine peptidases involved in protein turnover and homeostasis, as well as pathological conditions, such as cancer. We show that CAPE and CGA inhibit both peptidases, while CA shows a preference for cathepsin B, resulting in the strongest inhibition among these combinations. All compounds are linear (complete) inhibitors acting via mixed or catalytic mechanisms. Cathepsin B is more strongly inhibited at pH 7.4 than at 5.5, and CA inhibits its endopeptidase activity preferentially over its peptidyl-dipeptidase activity. Altogether, the results identify the CA scaffold as a promising candidate for the development of cathepsin B inhibitors, specifically targeting its endopeptidase activity associated with pathological proteolysis of extracellular substrates.

Keywords: caffeic acid phenethyl ester; catalytic inhibition; chlorogenic acid; enzyme inhibition; mixed inhibition; peptidase; proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caffeic Acids / chemistry
  • Caffeic Acids / pharmacology*
  • Cathepsin B / antagonists & inhibitors*
  • Cathepsin B / metabolism
  • Cathepsin L / antagonists & inhibitors*
  • Cathepsin L / metabolism
  • Chlorogenic Acid / chemistry
  • Chlorogenic Acid / pharmacology*
  • Drug Discovery
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Phenylethyl Alcohol / analogs & derivatives*
  • Phenylethyl Alcohol / chemistry
  • Phenylethyl Alcohol / pharmacology
  • Proteolysis / drug effects


  • Caffeic Acids
  • Enzyme Inhibitors
  • Chlorogenic Acid
  • CTSB protein, human
  • Cathepsin B
  • CTSL protein, human
  • Cathepsin L
  • caffeic acid phenethyl ester
  • Phenylethyl Alcohol
  • caffeic acid