Ezetimibe Repurposing: An In-SilicoTesting of its Potential Anti-giardia Activity

Giardia leads to human parasitic disease, and it is highly prevalent in the developing countries. The current medication used to treat giardia is associated with numerous side effects. Moreover, the problem of the emerging giardia resistance given the limited number of anti-giardia agents. Ezetimibe is a cholesterol lowering agent, and it acts to inhibit cholesterol absorption. Giardia needs cholesterol for its survival. It is also known that Giardia depends on external sources of cholesterol. Interfering with the cholesterol uptake pathway might be a promising approach in Giardia therapeutics. Searching for new potential therapeutic targets and agents was the main objective of this research. The hypothesis we proposed is that Ezetimibe might have an inhibitory and/or killing effect on Giardia. Our aim was to test in-silico the potential anti-giardia activity of this drug and the possible targets. Literature as well as public databases search was done to find possible targets for Ezetimibe in Giardia. 3D Models for the found potential targets were generated using comparative modeling software. Models refinement and assessment were also done. Using Surflex-dock the possible binding of Ezetimibe to the giardia targets was tested. We found that a putative Lecithin-cholesterol acyltransferase (LCAT) and a putative Giardia lamblia low-density lipoprotein receptor related protein could be  possible targets for this drug. The docking score on LCAT was fair. By binding to one or both of these proteins, Ezetimibe might be able to affect Giardia viability. In vitro validation of this result is yet to be done.