High-throughput Drug Repositioning for the Discovery of New Treatments for Chagas Disease

Abstract

Despite affecting around 8 million people worldwide and representing an economic burden above $7 billion/ year, currently approved medications to treat Chagas disease are still limited to two drugs, nifurtimox and benznidazole, which were developed more than 40 years ago and present important efficacy and safety limitations. Drug repositioning (i.e. finding second or further therapeutic indications for known drugs) has raised considerable interest within the international drug development community. There are many explanations to the current interest on drug repositioning including the possibility to partially circumvent clinical trials and the consequent saving in time and resources. It has been suggested as a particular attractive approach for the development of novel therapeutics for neglected diseases, which are usually driven by public or non-profit organizations. Here we review current computer-guided approaches to drug repositioning and reports on drug repositioning stories oriented to Chagas disease, with a focus on computer-guided drug repositioning campaigns.

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

“…Unfortunately, after a recent evaluation of their effectiveness, none of these alternatives was successful [56,57] highlighting the urgent need for the development of new therapeutic substitutes for conventional treatments. In this context, drug repositioning is a rapid way to obtain compounds with new desired biological activity from drugs already approved for human use, smoothing the path for quickly reaching the counters [58]. Within in silico strategies for drugs identification, the combination of different virtual screening techniques significantly enhances the possibility to succeed in subsequent in vitro and in vivo studies [18].…”

Cascade Ligand- and Structure-Based Virtual Screening to Identify New Trypanocidal Compounds Inhibiting Putrescine Uptake

“…In this particular case, the drug has been identified as trypanocidal agent within our research group, during an in silico screening to detect novel cruzipain inhibitors. The drug later confirmed its potential both in acute and chronic rodent models of Chagas disease (Bellera et al, 2015 ; Sbaraglini et al, 2016 ). In that occasion, though, it was observed that the potency of the drug against the parasite was higher than the inhibitory potency against cruzipain, suggesting multiple mechanisms of action besides cruzipain inhibition.…”

“…Table 2 shows the hits selected through the combined ligand- and target-based approach, including the PPV range for the correspondent score value of the 8-model ensemble between Ya values of 0.001 and 0.010. Note that 3 of the hits, namely clomifene, oxiconazole and clofazimine have previously been assayed against T. cruzi , with positive results (Sykes and Avery, 2013 ; Bellera et al, 2015 ; Kaiser et al, 2015 ). Most of the compounds have a docking score lower than the value found for the natural ligand putrescine (− 6.0 ), which was calculated previously in the same docking conditions.…”

“…Drug repositioning (also known as drug repurposing, indication expansion and indication shift) represents an interesting strategy to approach the development of new medications for NTD (Ekins et al, 2011 ; Bellera et al, 2015 ; Ferreira and Andricopulo, 2016 ; Sbaraglini et al, 2016 ). It consists in finding novel medical uses for existing drugs, including approved, experimental, discontinued and shelved drugs.…”

Lopinavir and Nelfinavir Induce the Accumulation of Crystalloid Lipid Inclusions within the Reservosomes of Trypanosoma cruzi and Inhibit Both Aspartyl-Type Peptidase and Cruzipain Activities Detected in These Crucial Organelles

“…In the study of Bellera and coworkers [ 31 ], the authors applied the computation of molecular topological descriptors and linear discriminant analysis for the search of novel compounds against T. cruzi , focusing on cruzipain as the main parasite target. Among the compounds preselected, the HIV-PI saquinavir was one of them, where docking studies and simulations predicted interactions with cruzipain.…”