Structure-Based Drug Development Against Malaria

The protozoon Plasmodium falciparum is the causative agent of tropical malaria which causes up to three million human deaths and up to 500 million episodes of clinical illness throughout the world annually. Children in African countries bear the largest part of this burden. Due to the rapid development of resistance to clinically used drugs like chloroquine and mefloquine and the increasing risk of resistance to artemisinins, novel effective and affordable antimalarial agents are urgently required. The progress made over the last years in the fields of genomics, proteomics, and clinical medicine coupled with improved facilities as well as technical progress in structural biology and high throughput screening methods are essential to support these drug development approaches. Furthermore concerted programs supported by governments, industry and academia contribute significantly to the progress in the field of antimalarial chemotherapy. Among the most interesting antimalarial target proteins currently studied are proteases, like plasmepsins, falcipains and falcilysin, but also protein kinases, glycolytic enzymes and enzymes involved in lipid metabolism and DNA replication. In addition, redox active proteins like glutathione reductase, thioredoxin reductase and glutathione S-transferase have become increasingly interesting. In this article we summarize the major current structure-based antimalarial drug development approaches. We briefly review the presently available three-dimensional structures of Plasmodium proteins together with their potential as drug targets. In parallel, we give an overview over inhibitors that have been developed on the basis of these known parasite protein structures or related structures of proteins from other organisms.