Abstract
Although many new anti-infectives have been discovered and developed solely using phenotypic cellular screening and assay optimization, most researchers recognize that structure-guided drug design is more practical and less costly. In addition, a greater chemical space can be interrogated with structure-guided drug design. The practicality of structure-guided drug design has launched a search for the targets of compounds discovered in phenotypic screens. One method that has been used extensively in malaria parasites for target discovery and chemical validation is in vitro evolution and whole genome analysis (IVIEWGA). Here, small molecules from phenotypic screens with demonstrated antiparasitic activity are used in genome-based target discovery methods. In this Review, we discuss the newest, most promising druggable targets discovered or further validated by evolution-based methods, as well as some exceptions.
Highlights
Malaria is the most prevalent parasitic disease in man
The World Health Organization (WHO) estimated 216 million cases and 445 000 deaths in 2016 globally, out of which 91% were in Africa alone and 99% were due to Plasmodium falciparum infections (WHO, World Malaria Report 2017)
The recent dramatic increase in novel druggable pathways in Plasmodium parasites has been facilitated largely by the utilization of in vitro resistance evolution combined with mutation identification through a variety of genomic techniques
Summary
One of the first novel targets that was discovered with IVIEWGA was PfATP4, a P. falciparum p-type cation ATPase It was first identified as the target of the spiroindolone compound, KAE609 ( called NITD609), which is commercially called Cipargamin.[6] KAE609 is highly active against both blood-stage P. falciparum and P. vivax field isolates and culture-adapted isolates with single-digit nanomolar IC50s.7. Despite the different location of the mutations, SJ733-resistant lines are cross-resistant to spiroindolones.[12] SJ733 causes an increase in the parasite’s cytosolic Na+ level and concurrent alkalinization of the cytosol which seems in line with the loss of PfATP4 activity.[12] The overrepresentation of PfATP4 inhibitors in many phenotypic screens may be because PfATP4 is a high-value target whose inhibition results in rapid death, even at low inhibitor concentrations.[12] its localization to the parasite plasma membrane may make it a more accessible target since membrane permeability of inhibitors would not be necessary for drug efficacy. A well-known class of targets in other species, which has become increasingly relevant due to multiple discoveries using IVIEWGA in Plasmodium, is the tRNA synthetase family
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