Inhibition of Protein-Protein Interactions

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Protein-protein interactions are essential to all cellular processes. Often, protein-protein interactions initiate signaling events that control metabolic pathways. Development of the ability to modulate these processes will result in major scientific breakthroughs in biology. Ideally, small molecule modulators will be preferred; however, the scientific knowledge and the appropriate strategies for designing them are still lacking. The major goal of this project is to develop the technologies required to identify and modify the behavior of initiation points for protein signaling. These points define the specific sites to be targeted by small molecules. By identifying sites that are uniquely associated with signaling and not binding, the technology will allow the development of design strategies for energy efficient modulators; i.e. molecules that will perform their function without the need for disrupting protein-protein binding, and therefore expending unnecessary energy. During the next five years, the experimental aspects of the research will focus on the inhibition of an allosteric activation triggered by a protein-protein interaction. This type of protein-protein interaction defines an initial event in cell penetration of a virus and will be used to implement and optimize the technology prior to implementation in other systems. The broader impacts resulting from this research include different fronts. At the practical level, it provides new strategies for designing small molecules that can modulate biological signaling. These intellectual advances may lead to important applications in areas such as synthetic biology, information transfer in biological systems and regulatory networks. It must be noted that the technologies required for engineering inhibitors or activators of signaling triggered by protein-protein interactions are not yet available. The broader impact is, however, not limited to the potential applications of the scientific discoveries. Graduate and undergraduate students will benefit from this project by the incorporation of these subjects in the courses taught by the PI. Also this project will allow the participation of undergraduate students in a state-of-the-art research project. The PI presents about 20 seminars per year at universities, colleges, research laboratories as well as national and international meetings. As part of the outreach program, the PI's laboratory donated a fully functional Isothermal Titration Calorimetry to Brynn Mawr College in Pennsylvania and trained faculty and students. These activities will continue and will be expanded during the next five years of funding.