Inhibitors of cruzipain and cathepsin L

Abstract

Cysteine proteases represent important molecular targets for the development of antiparasitic chemotherapy. Cruzipain (cruzain), a cathepsin L-like member of the C1 (papain) family of endopeptidases, is the major cysteine protease of Trypanosoma cruzi, the protozoan etiologic agent of Chagas’ disease. Chagas’ is the leading cause of heart disease in Latin America. Here we report the biochemical evaluation of a series of new compounds designed to inhibit cruzipain. More than twenty thiosemicarbazones containing α, and β-tetralones, chroman-4-ones, thiochroman-4-ones, 3-bromophenylcyclopentanones and 3-bromophenylcyclohexanones were synthesized. Several of these compounds inhibited recombinant cruzain with IC50 values in the low nM range using the fluorogenic substrate, Cbz-Phe-Arg-7-amino-4-methylcoumarin. This series of compounds was also tested against cathepsin L, one of the major cysteine proteases found in and secreted from animal tissues. Cathepsin L is of particular interest because of reports of its involvement in the development of rheumatoid arthritis and the suggested role of the enzyme in tumor invasion and metastasis. A number of the semithiocarbazone compounds were very effective inhibitors of cathepsin L. The authors thank Elizabeth Hansell and Dr. James McKerrow for the gift of cruzipain and the Vice-Provost for Research of Baylor University, the Welch Foundation and Oxigene, Inc. for support.