Given the major differences observed in parasite epigenetic featu

Given the major differences observed in parasite epigenetic features compared with all other eukaryotic organisms, inhibitors developed against Plasmodium-specific epigenetic enzymes have a strong potential for new therapeutic strategies against P. falciparum. Many of the current drug therapies are based on chemically engineered variants of already known antimalarial compounds (e.g. aminoquinolines and/or peroxides). Intensive exploration of the P. falciparum genome

has lead to the identification CYC202 of parasite-specific essential genes or metabolic pathways that could be targeted for rational drug designs (18,23,60,62,91–93). For example, a fosmidomycin-sensitive mevalonate-independent pathway of isoprenoid biosynthesis, absent from higher eukaryotes and located in the plant plastid-like parasite organelle namely the

apicoplast, was identified in P. falciparum (94). Along with the discovery of new drug targets, the discovery of mechanisms of drug resistance has been significantly refined using genome-wide analysis. Typically, mechanisms of drug resistance are determined by examining the genetic differences between sensitive and resistant strains. The best-studied case of drug resistance in P. falciparum is chloroquine resistance (CQR). Chloroquine resistance is mediated by a transporter Dorsomorphin clinical trial gene (Pfcrt) and by the multidrug resistance gene (Pfmdr1). The discovery of the genes associated with CQR took years of heavy molecular, epidemiology and genetic studies. Research is still ongoing to fully comprehend CQR in the parasite. Today, whole-genome analytic tools provide the capability of analysing rapidly the genetic changes that occur in the genome of a resistant strain. Whole-genome G protein-coupled receptor kinase scanning using tiling microarrays has already been used for this purpose. For example, initial analyses found relatively abundant copy number variations in P. falciparum -resistant strains (5). Point mutations in the apicoplast were recently associated with resistance to clindamycin, a drug used in combination with quinine for the treatment

of malaria in pregnant women and infants (95). Another striking example of the power of genomics in drug discovery is the identification of a potent drug by cell proliferation–based compound screening (96) followed by the discovery of one of its targets using high-density microarrays and sequencing (97). Without the advent of genomics, such a process would have required many years. All together, it is likely that these genome-wide approaches will soon uncover mechanism of drug resistance including emerging resistance of artemisinin. To further highlight the power of genomic studies for the discovery of new effective antimalarial strategies, a recent genome-wide SNP analysis identified regions of high and low recombination frequencies (hot spots and cold spots).

Leave a Reply

Your email address will not be published. Required fields are marked *


You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>