Target identification and validation of novel antimalarials

It has been recognized that new antimalarials with a novel mode of action are critical to combat the continued emergence and dissemination of drug-resistant parasites that threaten the efficacy of current malaria treatments. Thus, recent high-throughput screening campaigns have been initiated using asexual intraerythrocytic stage cell-based assays of Plasmodium falciparum. These have led to the unprecedented identification of over 10,000 new antimalarial compounds. Inherently, novel compounds identified by cell-based assays will have poorly defined modes of action. While some of these compounds may have recognizable targets, the majority of cell-based hits are comprised of unique chemical scaffolds usually lacking cross-resistance with known drugs. It is likely that these novel antimalarial scaffolds will reveal new targets. A challenge for the community will be to assign these small molecules to their targets. In this article, we review methodologies to assist in the determination of a compound's mode of action.