title: [Trypanocidal effect of cysteine protease inhibitors in vitro and in vivo in experimental Chagas disease].
abstract: Endemic in most American countries, Chagas' disease causes high morbidity and mortality. Recent experimental and clinical evidence shows the importance of chemotherapy in both the acute and chronic phases of this disease. However, treatment is yet limited by the toxicity associated to available drugs. This review describes the design, evolution, and selection of dipeptides that interrupt the intracellular cycle of T. cruzi and cure acute experimental infections in laboratory animals. Peptido-mimetic inhibitors specifically bind cruzain, a T. cruzi cystein protease. The inhibitors cause alterations in the Golgi complex and ER, accumulation of unprocessed enzyme within Golgi cisternae, and decrease of mature cruzain within lysosomes. The most effective compound, N-Pip-F-hF-VS phi, cured an acute lethal infection in experimental animals. Myocardial lesions, lymphocyte infiltration and intracellular amastigote clusers were absent in treated animals. Preliminary toxicology and pharmacokinetic analyses suggest the lack of toxicity associated to high doses and prolonged treatment regimes. Protease inhibitors may soon become good chemotherapeutic alternatives for acute and chronic Chagas' disease.
authors.affiliation: Department of Pathology, University of California, San Francisco, USA. jcengel@itsa.ucsf.edu
authors.forename: J C
authors.initials: JC
authors.lastname: Engel
authors.forename: P S
authors.initials: PS
authors.lastname: Doyle
authors.forename: J H
authors.initials: JH
authors.lastname: McKerrow
mesh_terms: D000208:Acute Disease; D000818:Animals; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D014355:Chagas Disease / Q000188:drug therapy* / Q000473:pathology; D002908:Chronic Disease; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D051379:Mice; D008809:Mice, Inbred C3H; D015800:Protozoan Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats
chemical_list: D000981:Antiprotozoal Agents; D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi