Thomas Zimmermann, Jiachen Feng, Luana Janaína de Campos, Lindsey A. Knight, Jan Schlötzer, Yesid A. Ramirez, Kevin Schwickert, Markus Zehe, Thomas B. Adler, Tanja Schirmeister, Caroline Kisker, Christoph Sotriffer, Martin Conda-Sheridan and Michael Decker*,
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引用次数: 0
Abstract
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.
期刊介绍:
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.