Identifying hypnozonticidal agents using chemogenomic, bioinfomatics and phenotypic strategies: focus in Plasmodium vivax

Abstract

Malaria is one of the most important public health problems in tropical and subtropical areas, with approximately 200 million cases worldwide annually. In Brazil, P. vivax is the most prevalent species, accounting for around 90% of all cases. Unlike P. falciparum parasite, whose continuous in vitro culture stablished in the mid-70s has given us significant advances in Falciparum Malaria pathogenesis; to date, little is known about P. vivax biology due to the absence of long-lasting techniques for laboratory culture. In 2007, more than 40 years after the first attempt to eradicate Malaria, this idea was brought to light again by a call from Bill & Melinda Gates Foundation aiming to eliminate all parasites able to cause the infection in humans. One of the major obstacles that hinder us to achieve this goal is the lack of information regarding Malaria Vivax pathogenesis, due to its high dissimilarity with the relatively well-known Falciparum Malaria. Among the several differences between these two parasites, we call attention to P. vivax quiescent liver stages, responsible for causing Malaria relapse following weeks, months or even years after parasite inoculation, without the need of mosquito intermediates: the hypnozoites. Currently, the little knowledge regarding hypnozoites came from studies using primary liver cells from monkeys infected with P. cynomolgi, the gold standard experimental model for P. vivax studies, due to their biogenetic resemblance. The only FDA approved drugs active against hypnozoites, Primaquine and Tafenoquine, have limited use due to the risk of hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), a common genetic deficiency. Within this context, the present project seek to identify compounds against molecular targets whose inhibition may tackle the latent stages of P. vivax. To this end, proteins that are essential for P. vivax and P. cynomolgi hypnozoite maintenance and maturation will be selected based on literature studies, and comparative genomics strategy will be applied to chosen candidates that are absent or with low similarity in humans. Subsequently, using homology modelling and molecular docking, virtual screenings will be performed in chemical libraries for hit identification. Promising molecules will be tested for cytotoxicity in mammalian cells and, for future directions, only compounds displaying good selectivity index will have their activity tested against other stages within, P. cynomolgi and P. vivax life cycle. In conclusion, the present project could help to identify new antimalarial therapies against Vivax Malaria. (AU)