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Inhibitors of cruzipain and cathepsin L
Author(s) -
Trawick Mary Lynn,
Chen ShenEn,
Arispe Milenka,
Siles Rogelio,
Zhou Ming,
Pinney Kevin G.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a51-a
Subject(s) - proteases , trypanosoma cruzi , cathepsin , biochemistry , cathepsin b , cysteine protease , chagas disease , chemistry , cathepsin l , cysteine , cathepsin c , cysteine proteinase inhibitors , enzyme , microbiology and biotechnology , biology , virology , caspase , apoptosis , parasite hosting , programmed cell death , world wide web , computer science
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 IC 50 values in the low n M 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.