Malaria remains a major health problem, especially because of the emergence
of resistant P. falciparum strains to artemisinin derivatives. In this context, safe and affordable
antimalarial drugs are desperately needed. New proteins have been investigated
as molecular targets for research and development of innovative compounds with welldefined
mechanism of action. In this review, we highlight genetically and clinically validated
plasmodial proteins as drug targets for the next generation of therapeutics. The enzymes
described herein are involved in hemoglobin hydrolysis, the invasion process,
elongation factors for protein synthesis, pyrimidine biosynthesis, post-translational modifications
such as prenylation, phosphorylation and histone acetylation, generation of ATP
in mitochondrial metabolism and aminoacylation of RNAs. Significant advances on proteomics,
genetics, structural biology, computational and biophysical methods provided
invaluable molecular and structural information about these drug targets. Based on this,
several strategies and models have been applied to identify and improve lead compounds.
This review presents the recent progresses in the discovery of antimalarial drug candidates,
highlighting the approaches, challenges, and perspectives to deliver affordable, safe
and low single-dose medicines to treat malaria.