Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning

ALBERCA LUCAS; SBARAGLINI MARIA LAURA; BALCAZAR DARIO; FRACCAROLI LAURA; CARILLO CAROLINA; MEDEIROS ANDREA; BENITEZ DIEGO; COMINI MARCELO; TALEVI ALAN

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN

SPRINGER

Lugar: Berlin; Año: 2016

0920-654X

Chagas disease is a parasitic infection causedby the protozoa Trypanosoma cruzi that affects about 6million people in Latin America. Despite its sanitaryimportance, there are currently only two drugs available fortreatment: benznidazole and nifurtimox, both exhibitingserious adverse effects and limited efficacy in the chronicstage of the disease. Polyamines are ubiquitous to all livingorganisms where they participate in multiple basic functionssuch as biosynthesis of nucleic acids and proteins,proliferation and cell differentiation. T. cruzi is auxotrophfor polyamines, which are taken up from the extracellularmedium 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 polyamineanalogs with and without inhibitory effect on T. cruzi wehave inferred classificatory models that were later appliedin a virtual screening campaign to identify anti-trypanosomalcompounds among drugs already used for othertherapeutic indications (i.e. computer-guided drug repositioning)compiled in the DrugBank and Sweetlead databases.Five of the candidates identified with this strategywere evaluated in cellular models from different pathogenictrypanosomatids (T. cruzi wt, T. cruzi PAT12, T.brucei and Leishmania infantum), and in vitro models ofaminoacid/polyamine transport assays and trypanothionesynthetase inhibition assay. Triclabendazole, sertaconazoleand paroxetine displayed inhibitory effects on the proliferationof T. cruzi (epimastigotes) and the uptake ofputrescine by the parasite. They also interfered with theuptake of others aminoacids and the proliferation ofinfective T. brucei and L. infantum (promastigotes). Trypanothionesynthetase was ruled out as molecular target forthe anti-parasitic activity of these compounds.