GRK 2243 "Understanding Ubiquitylation: From Molecular Mechanisms to Disease"

Project B5

Structure-based design and synthesis of antimicrobial DUB inhibitors

Michael Decker, Christoph Sotriffer, Caroline Kisker

Upon bacterial infection, host cells activate apoptotic pathways to limit pathogen replication. Consequently, efficient proliferation of the obligate intracellular pathogen Chlamydia trachomatis, a major cause of trachoma and sexually transmitted disease, depends on suppression of host cell apoptosis. C. trachomatis secrets the DUB Cdu1 into the host cell, leading to the stabilization of the anti-apoptotic protein Mcl-1 and, thus, suppression of host cell apoptosis. Bacterial DUBs are attractive, but yet underexplored targets for drug discovery against infectious diseases. Targeting the bacterial effector protein Cdu1 may, therefore, lead to new therapeutic possibilities. This project pursues a structure-based drug design approach to develop and synthesize highly active antimicrobial DUB inhibitors. Therefore, we want to establish a modular system, consisting of a library of recognition units and a set of warheads, for detailed investigation into DUB inhibition and fine-tuning of inhibition mechanisms.