Researchers have discovered the Achilles heel of the Plasmodium and aims a molecular arrow to destroy it.
The group led by Didier Picard, professor of biology at the Faculty of Sciences of UNIGE, Switzerland, is closely interested in the protein Heat Shock Protein 90 (HSP90), which plays a central role for several factors involved in the life cycle, survival and resistance of the pathogen.
Expressed in organisms as diverse as bacteria and mammal cells, HSP90 acts as a "chaperone", by helping other proteins during both normal and stressful periods.
Tai Wang, a PhD student at the Department of Cell Biology of UNIGE used ultra-sophisticated computerised modelling tools to characterise the various tridimensional conformations of the parasite's HSP90.
"The human chaperone harbours a "pocket" that binds molecules known to inhibit its activity. I compared it with that of the Plasmodium, hoping to find a difference which could be targeted by a specific inhibitor, but didn't," reported the researcher.
By studying the HSP90 of the pathogen from every possible angle, Wang found another pocket capable of binding inhibitory substances, completely absent in its human alter ego. Using a supercomputer, he performed the screening of a virtual library containing more than a million chemical compounds while retaining those that could fit in this pocket. This screening in silico led him to select five candidates.
These experiments were then completed by a "real time" modelling technique. "The simulations were conducted to analyse the dynamics of interaction between the HSP90 and the candidates, leading to the discovery of inhibitors which interact specifically with the Plasmodium falciparum chaperone".
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The molecules were then tested in vitro in different systems. The biologists demonstrated in particular the toxicity of those inhibitors on Plasmodium falciparum cultures, in doses sufficient to kill the parasites without affecting the infected red blood cells.
The study has been published in the Journal of Medicinal Chemistry.