title: Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning.
abstract: Chagas disease is a parasitic infection caused by the protozoa Trypanosoma cruzi that affects about 6 million people in Latin America. Despite its sanitary importance, there are currently only two drugs available for treatment: benznidazole and nifurtimox, both exhibiting serious adverse effects and limited efficacy in the chronic stage of the disease. Polyamines are ubiquitous to all living organisms where they participate in multiple basic functions such as biosynthesis of nucleic acids and proteins, proliferation and cell differentiation. T. cruzi is auxotroph for polyamines, which are taken up from the extracellular medium by efficient transporters and, to a large extent, incorporated into trypanothione (bis-glutathionylspermidine), the major redox cosubstrate of trypanosomatids. From a 268-compound database containing polyamine analogs with and without inhibitory effect on T. cruzi we have inferred classificatory models that were later applied in a virtual screening campaign to identify anti-trypanosomal compounds among drugs already used for other therapeutic indications (i.e. computer-guided drug repositioning) compiled in the DrugBank and Sweetlead databases. Five of the candidates identified with this strategy were evaluated in cellular models from different pathogenic trypanosomatids (T. cruzi wt, T. cruzi PAT12, T. brucei and Leishmania infantum), and in vitro models of aminoacid/polyamine transport assays and trypanothione synthetase inhibition assay. Triclabendazole, sertaconazole and paroxetine displayed inhibitory effects on the proliferation of T. cruzi (epimastigotes) and the uptake of putrescine by the parasite. They also interfered with the uptake of others aminoacids and the proliferation of infective T. brucei and L. infantum (promastigotes). Trypanothione synthetase was ruled out as molecular target for the anti-parasitic activity of these compounds.
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), Argentina, 47 & 115, B1900AJI, La Plata, Buenos Aires, Argentina.
authors.forename: Lucas N
authors.initials: LN
authors.lastname: Alberca
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), Argentina, 47 & 115, B1900AJI, La Plata, Buenos Aires, Argentina.
authors.forename: María L
authors.initials: ML
authors.lastname: Sbaraglini
authors.affiliation: Instituto de Ciencias y Tecnología Dr. César Milstein (ICT Milstein), Argentinean National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina.
authors.forename: Darío
authors.initials: D
authors.lastname: Balcazar
authors.affiliation: Instituto de Ciencias y Tecnología 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: Instituto de Ciencias y Tecnología 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 Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, 11400, Montevideo, Uruguay.
authors.forename: Andrea
authors.initials: A
authors.lastname: Medeiros
authors.affiliation: Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, 11400, Montevideo, Uruguay.
authors.forename: Diego
authors.initials: D
authors.lastname: Benitez
authors.affiliation: Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, 11400, Montevideo, Uruguay.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Comini
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), Argentina, 47 & 115, B1900AJI, La Plata, Buenos Aires, Argentina. atalevi@biol.unlp.edu.ar.
authors.forename: Alan
authors.identifier: http://orcid.org/0000-0003-3178-826X
authors.initials: A
authors.lastname: Talevi
mesh_terms: D019732:Amide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000981:Antiprotozoal Agents / Q000737:chemistry; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D003198:Computer Simulation; D058492:Drug Repositioning; D005978:Glutathione / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use; D009593:Nitroimidazoles / Q000737:chemistry / Q000627:therapeutic use; D011073:Polyamines / Q000737:chemistry* / Q000627:therapeutic use; D013095:Spermidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use; D013876:Thiophenes / Q000737:chemistry / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000472:pathogenicity; D014584:User-Computer Interface
chemical_list: D000981:Antiprotozoal Agents; D007093:Imidazoles; D009593:Nitroimidazoles; D011073:Polyamines; D013876:Thiophenes; C012333:glutathionylspermidine; C061131:sertaconazole; C044809:trypanothione; D019732:Amide Synthases; C064407:trypanothione synthetase; D005978:Glutathione; D013095:Spermidine; C009999:benzonidazole
keywords: Chagas disease; Drug repositioning; Paroxetine; Polyamines; Triclabendazole; Trypanosomatids virtual screening