Henock Befekadu, a junior chemistry major at Carleton College, developed and optimized a fluorescence polarization assay and synthesized novel antimalarial compounds.
Malaria is a mosquito-borne disease caused by Plasmodium parasites endemic to the tropics, especially sub-Saharan Africa. With the emergence of resistance to frontline malarial drugs, there is an unmet need for novel anti-malarial therapeutics with new mechanisms of action. The Broad offers the most cutting-edge research in all aspects of the biomedical sciences. The Broad’s highly collaborative nature leads to the development of new ideas, allowing for the ability to ask really tough questions. Through collaboration I was able to develop my skills in both chemistry and biochemistry, and gain a deep understanding of the drug development process.The immunosuppressive drug rapamycin, which binds to FK506 binding proteins (FKBPs), has been shown to have anti-malarial activity. FKBPs are ubiquitous enzymes across all life forms; humans have 14 FKBP isoforms while malaria has a single FKBP (FKBP35). FKBP35 is essential for Plasmodium viability and hence is an attractive target for therapeutics. Towards the goal of elaborating therapeutics targeting FKBP35, we have developed a fluorescence polarization assay to identify drug-like molecules that target FKBP35 without the immunosuppressive effects of rapamycin. By counter-screening hits against human FKBPs, compounds with higher selectivity for FBKP35 will be selected for further optimization. Ultimately, we will build a new library of novel anti-malarial compounds with demonstrated selectivity towards FKBP35.
Project: Characterization of novel anti-malarial therapeutics using fluorescence polarization
Mentors: Thomas Atack, Cancer Program; Donald Raymond, Center for the Development of Therapeutics (CDoT)