Identification of molecules with hypnozonticidal action based on chemogenomics, bioinformatics and phenotypic analyzes: focus on Plasmodium vivax

Malaria remains a serious public health problem in several tropical and subtropical regions of the world, with approximately 200 million cases annually. In Brazil, Plasmodium vivax is the main species, responsible for almost 90% of cases. Unlike the P. falciparum parasite, whose continuous in vitro culture established in the mid-1970s has given us significant advances in the biology and pathogenesis of Falciparum Malaria; until today little is known about Vivax Malaria due to the absence of long-lasting techniques for cultivating your parasite in the laboratory. In 2007, after more than 40 years of the first attempt to eradicate Malaria, this idea comes to the fore through a call from the Bill & Melinda Gates Foundation to eliminate all parasites that can cause infection in humans. The objective has as one of the main obstacles, the information gap on the biology and pathogenesis of Vivax Malaria due to the high dissimilarity with Falciparum Malaria; drawing attention to the quiescent stages of the parasites responsible for the relapse of the disease, the hypnozoites. Currently the little that is known about hypnozoites comes from studies using primary culture of monkeys infected with P. cynomolgi, the gold standard experimental model for the study of P. vivax due to its biogenetic similarity. The only FDA-approved drugs active against hypnozoite forms belong to the 8-aminoquinolone class, Primaquine and Tafenoquine. However, the use of these drugs is limited due to risks of hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, a relatively common genetic deficiency. For this, essential proteins for the maintenance and maturation of hypnozoites will be selected based on the literature, and later a comparative genomics strategy will be applied to select proteins from P. vivax and P. cynomolgi, which have low similarity with human proteins. Subsequently, using homology and docking modeling techniques, a virtual screening will be carried out in compound libraries. Subsequently, compounds that demonstrate good efficacy in the initial phenotypic assays will be tested in mammalian cells for cytotoxicity assessment, and in ex vivo isolates of P. vivax from Southeast Asia and the Amazon. For future work, molecules with inhibitory potential will have their hypnozonticidal activities determined by means of functional tests using a radical cure model established in P. cynomolgi.

Project details

P. vivax
Response Strategies

Jun 2020 — May 2021

Brazil