October 2013 – Tai Wang, PhD at the Department of Cell Biology, discovers the Achilles heel of the Plasmodium and shoots a molecular arrow to defeat it.
The malaria parasite is particularly pernicious because it easily develops a resistance to treatments. Moreover, there is no new drug against the pathogen and yet safe for humans. Tai Wang, a researcher in the lab of Professor Didier Picard, is gearing up to offer a solution to both problems, using a single molecule.
Modelling the target protein of Plasmodium
This potential treatment targets the Heat Shock Protein 90 (HSP90). Expressed in organisms as diverse as bacteria and mammals, HSP90 functions as a ‘chaperone’, assisting other proteins in normal times and in stress conditions. After an infection with Plasmodium, HSP90 protects the parasite’s proteins during the bouts of high fever triggered by its presence. The chaperone is also involved in the maturation of the pathogen in human red blood cells. “My goal was to determine whether there is a difference between the human and the parasitic form of HSP90, which could be exploited for therapeutic purposes”, explains Tai Wang.
The PhD student has used ultra sophisticated tools for computer modelling to characterize the various three-dimensional conformations of the parasite’s HSP90. “There is a ‘pocket’ in the human chaperone that binds molecules that inhibit its activity. I compared it to that of the Plasmodium, hoping to find a difference that could be targeted by a specific inhibitor, but to no avail”, says the researcher.
A screening fully performed in silico
It was while scrutinizing the pathogen’s HSP90 from every possible angle that Tai Wang discovered an adjacent pocket capable of binding inhibitors, completely absent in its human alter ego. He performed a screening for potential inhibitors with the Blue Gene/P Supercomputer. “The simulations allowed me to analyze the dynamics of interaction between HSP90 and candidate treatments and to find an inhibitor that specifically interacts with the Plasmodium’s chaperone”.
This molecule was then tested in vitro in different systems. The biologist has in particular demonstrated the toxicity of the inhibitor on cultured Plasmodium. He also just discovered a dose capable of killing parasites that does potentially not represent a threat to the mammalian cells tested.
And what about the two patents and the future publication planned? “It’s pending”, says the student with a smile.
Molecular dynamics simulation of an HSP90 – inhibitor complex