Identification of new antimalarial drugs through chemogenomics strategy for repositioning and experimental validation

Human malaria parasites are responsible for the deaths of more than one million children each year. The absence of a vaccine, a shortage of effective new treatments and resistance of the parasites to the compounds currently available, underline the urgent need to identify new antimalarial therapies. A comparative genomic strategy using the TDR Targets and PlasmoDB databases will be applied to produce a list of therapeutic targets present in P. falciparum and P. vivax, but absent in humans, in order to increase inhibitory selectivity and decrease the likelihood of toxicity to humans. Subsequently, primary protein sequences selected as potential therapeutic targets will be used to interrogate different databases available to the public on the web that provide synoptic data on drugs and their targets, namely DrugBank, STITCH3.1 and Therapeutic Targets Database (TTD). This process will allow the identification of several drugs with inhibitory potential by predicting interactions with a specific target by means of homology criteria with previously determined therapeutic targets. The drugs thus identified will still be subject to further filtering criteria by bioinformatic methods that include pairwise alignment, functional region conservation status, BLAST chemical space analysis and principal component analysis (PCA). The biocomputational strategy described above will generate a list of drugs with high probabilities of being effective against malaria parasites. The actual antimalarial efficacy of these drugs will then be evaluated in in vitro experimental trials with P. falciparum and P. vivax through the in vitro susceptibility microtest using the [3H] -hypoxanthine incorporation method and the DELI-Test technique respectively . Subsequently, drugs that demonstrate good in vitro activity (IC 50≤ 1μM) will be evaluated in vivo using the experimental model of malaria Plasmodium chabaudi.

Drug-based Strategies
P. vivax

Jan 2015 — Jan 2018

Brazil