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

Upon infection by an intracellular pathogen, host cells activate apoptotic pathways to limit pathogen replication. Consequently, efficient proliferation of the obligate intracellular pathogen , a major cause of trachoma and sexually transmitted diseases, depends on the suppression of host cell apoptosis. secretes deubiquitinase ChlaDUB1 into the host cell, leading among other interactions to the stabilization of antiapoptotic proteins and, thus, suppression of host cell apoptosis.

Combined In-Solution Fragment Screening and Crystallographic Binding-Mode Analysis with a Two-Domain Hsp70 Construct.

Heat shock protein 70 (Hsp70) isoforms are key players in the regulation of protein homeostasis and cell death pathways and are therefore attractive targets in cancer research. Developing nucleotide-competitive inhibitors or allosteric modulators, however, has turned out to be very challenging for this protein family, and no Hsp70-directed therapeutics have so far become available. As the field could profit from alternative starting points for inhibitor development, we present the results of a fragment-based screening approach on a two-domain Hsp70 construct using in-solution NMR methods, together with X-ray-crystallographic investigations and mixed-solvent molecular dynamics simulations.

Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97.

Biosensor techniques have become increasingly important for fragment-based drug discovery during the last years. The AAA+ ATPase p97 is an essential protein with key roles in protein homeostasis and a possible target for cancer chemotherapy. Currently available p97 inhibitors address its ATPase activity and globally impair p97-mediated processes.

Characterization of binding properties of ephedrine derivatives to human alpha-1-acid glycoprotein.

Most drugs, especially those with acidic or neutral moieties, are bound to the plasma protein albumin, whereas basic drugs are preferentially bound to human alpha-1-acid glycoprotein (AGP). The protein binding of the long-established drugs ephedrine and pseudoephedrine, which are used in the treatment of hypotension and colds, has so far only been studied with albumin. Since in a previous study a stereoselective binding of ephedrine and pseudoephedrine to serum but not to albumin was observed, the aim of this study was to check whether the enantioselective binding behavior of ephedrine and pseudoephedrine, in addition to the derivatives methylephedrine and norephedrine, is due to AGP and to investigate the influence of their different substituents and steric arrangement.

Sesquiterpenes and sesquiterpenoids harbor modulatory allosteric potential and affect inhibitory GABA receptor function in vitro.

Naturally occurring compounds such as sesquiterpenes and sesquiterpenoids (SQTs) have been shown to modulate GABA receptors (GABA Rs). In this study, the modulatory potential of 11 SQTs at GABA Rs was analyzed to characterize their potential neurotropic activity. Transfected HEK293 cells and primary hippocampal neurons were functionally investigated using electrophysiological whole-cell recordings.

Antimicrobial Silver Multilayer Coating for Prevention of Bacterial Colonization of Orthopedic Implants.

Due to increasing rates of periprosthetic joint infections (PJI), new approaches are needed to minimize the infection risk. The first goal of this study was to modify a well-established infection model to test surface-active antimicrobial systems. The second goal was to evaluate the antimicrobial activity of a silver multilayer (SML) coating.

Investigation of orally delivered carbon monoxide for postoperative ileus.

Endogenously produced carbon monoxide (CO) has antioxidant and anti-inflammatory effects which is why CO has been investigated as a possible therapeutic agent for inflammatory disorders in different body systems, including the gastrointestinal (GI) tract. In an effort to develop an easy to use platform for CO delivery to the GI tract, we recently introduced the Oral CO Release System (OCORS) and demonstrated its preventive effect for experimental colitis in a rodent model. Building off on a comprehensive preclinical dataset on efficacy of inhaled and intraperitoneal CO in reducing postoperative ileus (POI), which is being defined as GI transit retardation after abdominal surgery, we evaluated an adapted OCORS platform to ameliorate POI by local CO delivery to the murine small intestine.

Controlled therapeutic gas delivery systems for quality-improved transplants.

Therapeutic gases enriched into perfusion solutions have been effectively used for the improvement of organ transplant quality. At present, the enrichment of perfusion solutions with gases requires complex machinery/containers and handling precautions. Alternatively, the gas is generated within the perfusion solution by supplemented carbonylated transition metal complexes with associated toxicological concerns when these metals contact the transplant.