Computer-aided drug repositioning for the treatment of Leishmaniasis

LUCAS N. ALBERCA; MARÍA L. SBARAGLINI; ANDREA MEDEIROS; DIEGO BENÍTEZ; MARCELO COMINI; ALAN TALEVI

Toledo

Conferencia; 6th World Congress on Leishmaniasis; 2017

DNDi

1 . BackgroundLeishmaniasis is neglected disease caused by the Leishmania parasites which are transmitted by the bite of infected female phlebotomine sandflies. Worldwide there are about 12 million people infected and is estimated that 30000 deaths occur annually. The most used drugs for the treatment of leishmaniasis are very toxic and display drug resistance. For this reason there is a need to find new drugs that can overcome these limitations.An important target on trypanosomatids is the polyamine metabolism. The polyamines are synthesized (or transported) and incorporated into trypanothione, the major redox cosubstrate of trypanosomatids. Because the enzymes of the polyamine metabolism are essential to parasite survival, the inhibition of some of these enzymes increases the chances to find new drugs against leishmaniasis.2 . MethodsWe have compiled a compound database containing polyamine analogs with and without inhibitory effect on Trypanosoma cruzi (a trypanosomatid). From this, we have inferred computational models capable of identifying compounds that inhibit the polyamine metabolism. These models were applied in a virtual screening campaign to identify anti-trypanosomatids compounds among drugs already used for other therapeutic indications (i.e. computer-guided drug repositioning).We have tested the biological activity of the candidates towards trypanosomatids determining the % of inhibition at 5uM and the half-maximal growth inhibition concentration (EC50) of the drugs. Additionally, we have realized a trypanothione synthetase (TryS) enzymatic assay to determine if the drugs inhibit this target.3. ResultsWe have obtained a model ensemble that has a very good predictive capability. After screening we have found 45 approved drugs as possible inhibitors of the polyamine metabolism. Five of these candidates were evaluated in cellular models from T. cruzi, T. brucei and L. infantum. 3 drugs displayed inhibitory effects on the proliferation of these trypanosomatids, and one of these drugs showed an EC50 of 2.2uM on L. infantum promastigotes. None of the compounds displayed activity on TryS, excluding this as major target of their biological activity.4 . ConclusionsThese results highlight the importance of the strategy followed since we could find active compounds with a minimal investment of time and money. So, computer ? guided drug repositioning provides cost- and time- efficient solutions for neglected tropical diseases, such as Leishmaniasis.