Boskovic Pilot Project Summary
Type 3 secretion system is a molecular machine used by the bacteria of several species in the initial steps of invasion of human cells. We are at the critical point at which we have gathered a sufficient structural information about the proteins comprising this machine to begin designing small molecules capable of binding and potentially interfering with its intended function. This project builds on previous discoveries of weak fragment binders to the proteins forming the tip of this system made by DeGuzman lab. We will first build a model of binding of experimentally identified weak binders by considering electrostatic surface of IpaD and SipD proteins. This model will allow us to introduce changes to the known fragment with a particular emphasis on the introduction of three-dimensionality by incorporating stereocenters into the structures of newly-prepared analogs. Access to both enantiomers (mirror images) of these structures would allow us to test the stereospecificity of binding, which is an important indication for further elaboration of these fragments. Finally, we will develop a solution for the general problem of linking weak fragments identified in this and similar experiments by protein-templated linking of two fragment molecules. Taken together, successful completion of these aims would not only aid in "drugging" the type 3 secretion system, but would also solve a long-standing issue in fragment-based drug discovery - achieving successful linking of the weak binders into a more potent combination of them.