Development of Falcipain-2 Inhibitors as Antimalarial Agents

Published by Gus Rosania on 18 December 2007 - 1:28pm

The development of falcipain-2 inhibitors as antimalarial agents is a collaborative Open Science project that we are joining. Our research group studies the development of small molecule chemotherapeutic agents that are targeted to specific sites-of-action, at a microscopic level. Falcipain-2 is a lysosomal enzyme of Plasmodium, the parasite that causes malaria. Therefore, the ability to identify small molecule falcipain-2 inhibitors that accumulate in the lysosomes of the parasite while not accumulating in other parts of the human body is key if the chemotherapeutic agents under development are going to have potent antimalarial activity in vivo, with minimal side effects.

Remarkably, the design of small molecule drugs targeted to microscopic sites of action (ie. specific organelles) within cells is in its infancy. Although the importance of the site of action in the context of drug design and development should be obvious, current rational design strategies used in the pharmaceutical industry focus on optimizing a drug's mechanism of action (ie. the binding of a drug to its specific molecular target and its inhibitory activity), because little is known about how to direct small molecule to the site of action. In our research group, we are developing cell-based molecular transport simulations, which allow prediction of how the chemical structure of small molecules lead to differential accumulation in various organelles of the cell. Therefore, one of the goals of this project is to combine results of such simulation, with data about target binding and target inhibitory activity, to determine which small molecule drug candidate is most likely to be effective and non-toxic in a cellular (and ultimately and organismic) context.

The student in charge of this project will be Jason Baik, a second year PhD student in the department of pharmaceutical sciences at the University of Michigan College of Pharmacy. As part of this project, Jason will be keeping a blog instead of the usual laboratory notebook.