title: Novel cruzipain inhibitors for the chemotherapy of chronic Chagas disease.
abstract: Despite current efforts worldwide to develop new medications against Chagas disease, only two drugs are available, nifurtimox and benznidazole. Both drugs require prolonged treatment and have multiple side effects and limited efficacy on adult patients chronically infected with Trypanosoma cruzi. Recently, computer-guided drug repositioning led to the discovery of the trypanocidal effects of clofazimine and benidipine. These compounds showed inhibitory effects on cruzipain, the major cysteine protease of T. cruzi, of different parasite stages and in a murine model of acute Chagas disease. The aim of this work was to determine the efficacy of these novel cruzipain inhibitors when administered in a murine model of chronic Chagas disease. Benidipine and clofazimine were able to reduce the parasite burden in cardiac and skeletal muscles of chronically infected mice compared with untreated mice as well as diminish the inflammatory process in these tissues. Further studies should be performed to study the synergism with benznidazole and nifurtimox in view of combined therapies.
authors.affiliation: Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences College, National University of La Plata (UNLP), 47 & 115 (B1900AJI) La Plata, Buenos Aires, Argentina. Electronic address: mlsbaraglini@biol.unlp.edu.ar.
authors.forename: María L
authors.initials: ML
authors.lastname: Sbaraglini
authors.affiliation: Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences College, National University of La Plata (UNLP), 47 & 115 (B1900AJI) La Plata, Buenos Aires, Argentina.
authors.forename: Carolina L
authors.initials: CL
authors.lastname: Bellera
authors.affiliation: Institute of Sciences and Technology Dr César Milstein (ICT Milstein), Argentinean National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina.
authors.forename: Laura
authors.initials: L
authors.lastname: Fraccaroli
authors.affiliation: Institute of Sciences and Technology Dr César Milstein (ICT Milstein), Argentinean National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina.
authors.forename: Luciana
authors.initials: L
authors.lastname: Larocca
authors.affiliation: Institute of Sciences and Technology Dr César Milstein (ICT Milstein), Argentinean National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina.
authors.forename: Carolina
authors.initials: C
authors.lastname: Carrillo
authors.affiliation: Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences College, National University of La Plata (UNLP), 47 & 115 (B1900AJI) La Plata, Buenos Aires, Argentina.
authors.forename: Alan
authors.initials: A
authors.lastname: Talevi
authors.affiliation: Department of Microbiology, School of Medicine, University of Buenos Aires (UBA), Instituto de Microbiología y Parasitología Médica (IMPaM-UBA CONICET), Buenos Aires, Argentina.
authors.forename: Catalina D
authors.initials: CD
authors.lastname: Alba Soto
mesh_terms: D000328:Adult; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000302:isolation & purification; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D002908:Chronic Disease / Q000188:drug therapy; D002991:Clofazimine / Q000008:administration & dosage* / Q000302:isolation & purification; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage* / Q000302:isolation & purification; D004195:Disease Models, Animal; D004358:Drug Therapy / Q000379:methods; D006801:Humans; D008297:Male; D008809:Mice, Inbred C3H; D009132:Muscles / Q000469:parasitology; D009543:Nifedipine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000302:isolation & purification; D059208:Parasite Load; D015800:Protozoan Proteins; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000981:Antiprotozoal Agents; D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; C050883:benidipine hydrochloride; D002991:Clofazimine; D003546:Cysteine Endopeptidases; C063214:cruzipain; D009543:Nifedipine
keywords: Benidipine; Chagas disease; Chronic phase; Clofazimine; Drug repositioning; Trypanosoma cruzi