|Publication Type||Journal Article|
|Year of Publication||2010|
|Authors||Weiwer, M, Mulrooney, C, Massi, D, Heidebrecht, R, Wiegand, R, Lukens, AK, Dick, J, Wirth, D, Ekland, E, Cheng, CC, Zhao, J, Yuan, J, Su, XZ, Johnson, RL, Guha, R, Dandapani, S, Munoz, B, Palmer, M, Thomas, C, Austin, CP, Fidock, D, Schreiber, SL|
Malaria, the most devastating of the parasitic diseases, afflicts an estimated 300-500 million people worldwide and results in more than 800,000 deaths annually. Several parasites in the genus Plasmodium infect humans, but Plasmodium falciparum has the most significant lethality. Drug resistance has compromised the efficacy of existing drugs. New antimalarial agents, especially agents that work against new targets in P. falciparum, are needed. As part of efforts to identify novel inhibitors of P. falciparum, we initiated a quantitative high-throughput screening (qHTS) campaign against the 3D7 line of P. falciparum. The robust whole parasite viability assay was screened against the Molecular Libraries Small Molecule Repository (MLSMR) as well as the Diversity-Oriented Synthesis (DOS) informer I library (approximately 8,000 compounds), which is a subset of the Broad Institute DOS library. From these efforts, we have identified a unique and novel structural class of antimalarial compounds from the Broad Institute DOS Informer I library. The probe (ML238) displayed picomolar activity in the SBYR live/dead assay against 3D7 and Dd2 P. falciparum. This activity was recapitulated in the luciferase assay, albeit at single-digit nanomolar activity, while showing no apparent mammalian cell cytotoxicity. The probe is in a novel structural class in the antimalarial field with unknown mechanism of action; therefore, this probe will be highly useful to the malaria research community in identifying new targets or developing new drug classes.