COMPUTER GUIDED DRUG REPOSITIONING FOR THE TREATMENT OF LEISHMANIASIS

ALBERCA L.; SBARAGLINI ML.; MEDEIROS A.; BENITEZ D.; COMINI M.; TALEVI A.

Toledo

Congreso; 6th World Congress on Leishmaniasis; 2017

Instituto de Salud Carlos III y Drugs for Neglected Diseases initiative (DNDi)

BackgroundThere are about 12 million people infected with Leishmaniasis worldwide, and it is estimated that 30,000 deaths occurannually. The most frequently used drugs for the treatment of leishmaniasis are very toxic and display drug resistanceissues, thus being a persisting need to find new drugs which overcome these limitations.Polyamine metabolism is a relevant target for the development of novel medications. Polyamines can be eithersynthesized or taken up from the medium and are essential precursors of trypanothione, the major redox cosubstrate oftrypanosomatids.MethodsWe have compiled a 268-compound database containing polyamine analogs with and without inhibitory effects ontrypanosomatids. From this dataset, we have inferred computational models capable of identifying compounds thatinhibit the polyamine metabolism. These models were applied in a virtual screening campaign on DrugBank andSweetlead databases, to identify active compounds against trypanosomatids among already known drugs used for othertherapeutic indications (i.e. computer-guided drug repositioning).We have tested the biological activity of the candidates towards Trypanosoma cruzi, Trypanosoma brucei andLeishmania infantum, determining the % of inhibition at 5 ?M and the half-maximal growth inhibition concentration(EC50). Additionally, we have tested in vitro their inhibitory potential towards trypanothione synthetase (TryS).ResultsThe in silico screening resulted in 45 hits predicted as possible inhibitors of the polyamine metabolism. Five of thesecandidates were evaluated in cellular models from T. cruzi, T. brucei and L. infantum. 3 drugs (triclabendazole,paroxetine and sertaconazole) displayed inhibitory effects on the proliferation of these trypanosomatids; one of them(paroxetine) showed an EC50 of 2.2 ?M on L. infantum promastigotes. None of the compounds displayed activity onTryS, excluding this as major target of their biological activity.ConclusionsThe results highlight the importance of the applied in silico strategy, since three active compounds were found with aminimal time- and resource-investment. Computer ? guided drug repositioning could efficiently provide solutions forneglected tropical diseases, such as Leishmaniasis.