Exploring the Merck library of natural product extracts to find and study potential new antimalarial agents
Malaria and other parasitic diseases are the greatest health problem currently facing the developing world, and P. falciparum malaria is a particularly severe problem in sub-Saharan Africa. Drug development is a necessary approach to reducing the worldwide impact of malaria, because it is the only approach that will benefit the millions of people currently afflicted with this disease. Natural products are a known, excellent source of antimalarial compounds. Two of the most effective antimalarial drugs (quinine and artemisinin) are natural products, and many synthetic antimalarial drugs are analogs of these two natural products.
This research combines the antimalarial exp0erise of the Kingston (VT) and the Cassera Groups (UGA) with the resources of the former Merck collection of natural product extracts now at the Natural Products Discovery Institute (NPDI). All 22,000 extracts from the NPDI are being assayed for antimalarial activity to identify active extracts. Extracts which pass rigorous selection criteria are then fractionated to isolate and determine the structures of the active compounds. Isolated compounds will be evaluataed for stage specific activity (asexual intraerythrocytic stages, gametocytocidal, and liver stages), leads will then be selected to elucidate their mode of action and potential molecular target(s) using proteomics, metabolomics and transcriptomics approaches, with the ultimate goal of find a novel antimalarial agent with a new mechanism of action.
Synthetic chemistry will provide analogs of these lead compounds for future drug development.
Examples of new compounds with activity against P. falciparum isolated by the Kingston group
Harinantenaina, L; Bowman, J. D.; Brodie, P. J.; Slebodnick, C.; Callmander, M. W.; Rakotobe, E.; Randrianaivo, R.; Rasamison, V. E.; Gorka, A.; Roepe, P. D.; Cassera, M. B.; Kingston, D. G. I. Antiproliferative and antiplasmodial dimeric phloroglucinols from Mallotus oppositifolius from the Madagascar dry forest. J. Nat. Prod. 2013, 76, 383-393.
Pan, E.; Gorka, A. P.; Alumasa, J. N.; Slebodnick, C.; Harinantenaina, L.; Brodie, P. J.; Roepe, P. D.; Randrianaivo, R.; Birkinshaw, C.; Kingston, D. G. I. Antiplasmodial and antiproliferative pseudoguaianolides of Athroisma proteiforme from the Madagascar dry forest. J. Nat. Prod. 2011, 74, 2174-2180.
Kingston, D. G. I. A natural love of natural products. J. Org. Chem. 2008, 73, 3975-3984.