Peptidyl and azapeptidyl methylketones as substrate analog inhibitors of papin and cathepsin B

Article abstract of DOI:10.1016/0223-5234(96)88312-7

Peptidyl methylketones containing Phe, Tyr, Tyr(I), Tyr(I2), Leu and Ile in P₂ were synthesized and tested as substrate analog revesible of papain and bovine spleen cathepsin B.The most effective cathepsin B inhibitor contained Tyr(I2) and displayed an inhibition constant of 4.7 μM at pH 6.8 and 25 deg C, while Leu or Ile gave practically inert analogs.Replacement of the amino acids in P₂ with the analogues α-azaamino acids, as well as the glycine in P₁ with α-azaglycine, led to complete loss of inhibiting activity.Introducing alkoxy substituents at themethyl adjacent to the ketone group generally resulted in more effective inhibitors, with inhibition constants in the micromolar range for both papin and cathepsin B. - Keywords: enzyme inhibiting activity; cysteine proptease; slow binding; peptidyl methylketone; azapeptidyl methylketone; papain; cathepsin B