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Matthias Rottmann, Tropical Institute
Written by Jackie Howard Tuesday, 08 May 2012 11:29
Taking “one step backwards” to accelerate malaria drug discovery
Malaria due to infection with Plasmodium spp. is one of the most devastating diseases in developing countries with 216 million cases in 2010, causing an estimated 655,000 deaths per year. For the treatment of malaria there are several highly active drugs available, like Chloroquine, Quinine, Mefloquine, Atovaquone, Artesunate and their analogs. Unfortunately by now to almost all of these drugs significant resistance has developed; even to the “last resort” Artemisinin-derivatives first cases of delayed clinical efficacy have been reported.
In the past decade the so called “rationale design” approach found its way into malaria drug discovery research. The availability of genome data and high-throughput systems for screening compounds was proclaimed as a milestone for discovering new anti-infective drugs. Molecular based approaches promised to identify new compounds that could inhibit key enzymes or cell receptors at submicromolar concentrations. Unfortunately, this promise has not been fulfilled. So the antiparasitic research community and its industrial partners took “one step backwards” to screening compounds against whole microorganisms. During the last few years, companies and their academic partners have screened several million compounds for antimalarial activity.
The NGBS consortium discovered several promising compounds with activity against the erythrocytic and hepatic stages of the malaria parasite. The discovery story of the Sprioindolones and the Imidazolopiperazines illustrates nicely the strength of a collaborative model and partnership between pharmaceutical companies and academic research institutions. One additional advantage of whole cell based screening is that it identifies compounds that may act on multiple molecular targets which might hamper and slow down the development of resistance. Furthermore cell-based screening is one way of finding new molecular targets that can help to develop drugs that block other stages of the parasite’s life cycle. In the context of malaria eradication it will be important to kill sexual stages of the parasite to stop transmission and to target dormant parasites in the liver of patients infected by Plasmodium vivax.
Matthias Rottmann, Ph.D.
Swiss Tropical and Public Health Institute