Antimalarial drugs in the pipeline

25 May 2010 - Pharmacochemistry

A gloomy report in the May 14 issue of Science asserts that antimalarial drug research is as good as dead. The most common malaria agent plasmodium falciparum has built up resistance to the well known drug chloroquine and even the drug of last resort artemisinin is under threat. In 2009 the global malaria death toll was over 800,000 people. According to Timothy Wells of the Medicines for Malaria Venture There are plenty of new leads, but none of them are even in phase I safety studies and they would take at least 7 or 8 years to get to the market.

Luckily new leads have been described in two articles in the May 20 issue of Nature. The first is by researchers from GlaxoSmithKline (Gamo et al. DOI) who in a very generous mood have shared the results of antimalarial testing of over 2 million organic compounds with the rest of the world. In their introduction the authors cite intrinsic difficulties in discovering and developing new antimicrobials, as well as a relative lack of public and private resource commitment towards antimalarial research as reasons for the lack in drug development progress. Another plausible reason one can think of is the poorly perceived profitability of antimalarial drugs by pharmaceutical companies because the usually third-world victims are expected to have little to spend.

Assembling over two million little labeled bottles each containing a promising drug is quite a logistical undertaking but fortunately from then on robots can take over. The experimental details are as we are known to expect from biochemical research are fuzzy but in simple terms the process starts by filling each well on a microtiter plate with a solution of falciparum infected red blood cells that apparently you can buy someplace. The drug is added and the mix is incubated. An effective drug kills the parasite and cell health is monitored by so-called LDH activity. An LDH developing solution containing a lactate is added which LDH if present converts to a pyruvate. In this process a NAD+ analog also present is reduced to the NADH analog which proton then migrates to nitro blue tetrazolium (also present) forming a bright-red formazan. In each plate the effective drugs can then be visually detected as distinct red spots. In this way more than 8,000 compounds were found to have activity against a particular multidrug resistant strain (at IC50).

In the second Nature article a collective of over 30 scientists from several non-profit institutions (Guiguemde et al 2010 DOI) accomplish a similar feat. Here the library contained over 300,000 chemical compounds with a yield of 561 compounds at EC50. The detection method used (this blog guesses) measures the activity of the polymerase chain reaction in healthy cells by adding SYBR Green I which only shows fluorescence when bound to double stranded DNA.
antimalarial drugs screening