The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases

Abstract

Historically, one of the key problems in neglected disease drug discovery has been identifying new and interesting chemotypes. Phenotypic screening of the malaria parasite, Plasmodium falciparum has yielded almost 30,000 submicromolar hits in recent years. To make this collection more accessible, a collection of 400 chemotypes has been assembled, termed the Malaria Box. Half of these compounds were selected based on their drug-like properties and the others as molecular probes. These can now be requested as a pharmacological test set by malaria biologists, but importantly by groups working on related parasites, as part of a program to make both data and compounds readily available. In this paper, the analysis and selection methodology and characteristics of the compounds are described.

Small Molecule Screen for Candidate Antimalarials Targeting Plasmodium Kinesin-5

“…This finding is supported by earlier work that showed this compound has no deleterious effect upon the growth and proliferation of HEK 293 cells in vitro (47). If this compound could cross-react with the human homolog, we would instead expect to see the classic Kinesin-5 loss of function mitotic catastrophe in the HEK 293 cells with subsequent cell cycle arrest with monopolar spindles (59).…”

“…Current criteria for potential transmission-blocking drugs posit that inhibition of the late stage gametocytes is equal to or better than targeting asexual stages. Several groups have pointed out that activity against early or late stage gametocytes does not guarantee that a compound will have transmission-blocking ability in the field or within in vivo models (47,61).…”

“…The NCI Diversity Set III compounds comprise a set of structurally well characterized and relatively rigid compounds that were selected on the basis of probing wide and distinct ranges of chemical space. The 400 MMV box compounds, on the other hand, have been shown to possess potent antimalarial activity against blood stage parasites of P. falciparum while not adversely affecting the growth of human cultured epidermal kidney cell lines (47). No target enzymes have yet been identified for any of the malaria box compounds, and no prior kinesin has formally been used to interrogate these specific chemical libraries.…”

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

“…More than 400,000 of those who died were African children (1). Recent successes in antimalarial drug discovery and development have led to renewed hope for global eradication of malaria (2,3). Antimalarial drugs are a critical component of the eradication campaign, and single-dose regimens of cheap, safe, and efficacious drugs, which ideally also reduce transmission, are required (4).…”

Discovering New Transmission-Blocking Antimalarial Compounds: Challenges and Opportunities

“…The Medicines for Malaria Venture (MMV) Malaria Box of 400 compounds (selectively active against asexual parasites [22]) has been screened worldwide for activity against stage IV/V gametocytes [20,[23][24][25][26][27][28][29][30][31]. Primary hit rates (>80% inhibition at 5 μM) of 4.5-24% [20,23,27,29] were achieved when screened against stage IV/V gametocytes; this increased to 33% against stage I-III gametocytes [23,26].…”