Structure-Based Design and Synthesis of Covalent Inhibitors for Deubiquitinase and Acetyltransferase ChlaDUB1 of Chlamydia trachomatis

Upon infection by an intracellular pathogen, 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 diseases, depends on the suppression of host
cell apoptosis. C. trachomatis secretes
deubiquitinase ChlaDUB1 into the host cell, leading among other interactions
to the stabilization of antiapoptotic proteins and, thus, suppression
of host cell apoptosis. Targeting the bacterial effector protein may,
therefore, lead to new therapeutic possibilities. To explore the active
site of ChlaDUB1, an iterative cycle of computational docking, synthesis,
and enzymatic screening was applied with the aim of lead structure
development. Hereby, covalent inhibitors were developed, which show
enhanced inhibition with a 22-fold increase in IC50 values
compared to previous work. Comprehensive insights into the binding
prerequisites to ChlaDUB1 are provided, establishing the foundation
for an additional specific antichlamydial therapy by small molecules.