Our laboratory is interested in how the expression of parasite genes changes during infection. The genome sequence of the African trypanosome became available in 2005 (a project in which the Center played a leadership role), but it is important to understand which genes are expressed in the stages of the parasite that causes disease and the stages that are transmitted. In our most recent project, we have been examining which proteins are synthesized during these important stages. Since proteins are the molecules that execute cellular processes, this information provides clues as to potential drug targets and to how the organism causes disease. The approach we are using is called ribosome profiling, which entails high throughput RNAseq of those mRNAs that directly producing proteins. These studies have already revealed that regulation of protein production is a large component of controlling which proteins are made in the pathogen.
The Parsons Lab is part of a consortium project to identify new drugs to treat toxoplasmosis. The project aims to create new compounds that specifically inactive a Toxoplasma gondii enzyme called CDPK1. This enzyme is a protein kinase, which modifies and activates other proteins important for the parasite to invade host cells where it can multiply. The active site of CDPK1 is different from the active sites of human protein kinases, and thus it has been possible to develop molecules that block the parasite but do not harm human cells. This collaborative project includes biochemists, structural biologists, chemists, pharmacologists, and parasitologists working together to accomplish our goals.
We are also pursuing a candidate drug target for African trypanosomiasis. This too is a protein kinase, and using genetic approaches, we have shown that it is essential to the parasite. As a proof of principle, we created parasites expressing a version of the kinase we engineers to be readily inhibited by a known compound and showed that chemical inhibition was rapidly toxic to the parasite both in vitro and in an infection model. These studies poise us to embark on a project to develop drugs that may prove useful to eliminate human African trypanosomiasis within the decade. Such inhibitors may additionally be applicable to Leishmania parasites, which infect 1.3 million people annually.