Malaria: targeting parasite and host cell kinomes.
Malaria still remains one of the deadliest infectious diseases, and has a tremendous morbidity and mortality impact in the developing world. The propensity of the parasites to develop drug resistance, and the relative reluctance of the pharmaceutical industry to invest massively in the developments of drugs that would offer only limited marketing prospects, are major issues in antimalarial drug discovery. Protein kinases (PKs) have become a major family of targets for drug discovery research in a number of disease contexts, which has generated considerable resources such as kinase-directed libraries and high throughput kinase inhibition assays. The phylogenetic distance between malaria parasites and their human host translates into important divergences in their respective kinomes, and most Plasmodium kinases display atypical properties (as compared to mammalian PKs) that can be exploited towards selective inhibition. Here, we discuss the taxon-specific kinases possessed by malaria parasites, and give an overview of target PKs that have been validated by reverse genetics, either in the human malaria parasite Plasmodium falciparum or in the rodent model Plasmodium berghei. We also briefly allude to the possibility of attacking Plasmodium through the inhibition of human PKs that are required for survival of this obligatory intracellular parasite, and which are targets for other human diseases.
Inserm U609/Wellcome Centre for Molecular Parasitology, University of Glasgow, 120 University Place, Glasgow G12 8TA, Scotland, UK. christian.doerig@epfl.ch
Christian
C
Doerig
Abdirahman
A
Abdi
Nicholas
N
Bland
Sylvain
S
Eschenlauer
Dominique
D
Dorin-Semblat
Clare
C
Fennell
Jean
J
Halbert
Zoe
Z
Holland
Marie-Paule
MP
Nivez
Jean-Philippe
JP
Semblat
Audrey
A
Sicard
Luc
L
Reininger
D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000201:enzymology; D010962:Plasmodium berghei / Q000201:enzymology*; D010963:Plasmodium falciparum / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D011494:Protein Kinases; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D011494:Protein Kinases