Nontraditional attack on the parasite that causes sleeping sickness
Molecular biologists Hans Westerhoff (UvA) and Barbara Bakker (VU) has designed a new method of finding treatments that inactivate disease-causing cells like cancer cells or parasites without causing collateral damage to healthy human cells. The proof of principle has now been published in Scientific Reports.
Many illnesses are caused by pathogens that divide quickly. Examples of such illnesses are infections by bacteria or parasites, but also cancer. New medicines are supposed to target the pathogen, but not healthy human cells. This task is difficult because of the molecular similarity between pathogen and healthy human cells.
Metabolism of sugars
Both the parasite and the host metabolize sugars to retrieve energy. Both do so using tools (enzymes) that are essentially identical and arranged in essentially the same pathway. Therewith it was held impossible to designate any of the enzymes of the parasite as drug target: both the parasite and the patient would succumb to the drug. The team used a systems biology finding to break this barrier: Even if two pathways and their enzymes are the same, the flux through them may be controlled at different enzymes. One reason is that the expression level of the enzymes may differ between the two pathways. Indeed, the research team now determined which enzyme is much more rate-limiting in the deadly parasite causing sleeping sickness (Trypanosoma brucei) than in human cells such as liver and red blood cells. According to this new ‘differential-network based drug design’ method, this enzyme should then be the best drug target.
The international research team, including Westerhoff and Bakker, have used computer simulations based on precise biochemical data to compare the sugar metabolism between the parasite and humans. They found a remarkable difference: when the researchers slowed down the enzyme that promotes the intake of sugar, the parasite suffered from an energy shortage, while the human cells seemed unaffected. Therefore, a drug that could slow down the intake of sugar, would target the parasite, but not cause collateral damage to human cells. Jurgen Haanstra then checked these predictions in the lab: parasites and human blood cells were placed together and received chemicals to slow down the intake of sugar. Indeed, only the parasites were killed by this treatment.
These results show that treatment can be developed that target networks in pathogens, but not the corresponding networks in healthy human cells. The next step is to make drugs reach the glucose intake system in parasites in the blood before the drugs are washed out or broken down by the liver. This method can be used to a wide variety of pathogens, including cancer.