Inhibition of Yersinia Tyrosine Phosphatase by Furanyl Salicylate Compounds

Abstract

To avoid detection and targeting by the immune system, the plague-causing bacterium Yersinia pestis uses a type III secretion system to deliver a set of inhibitory proteins into the cytoplasm of immune cells. One of these proteins is an exceptionally active tyrosine phosphatase termed YopH, which paralyzes lymphocytes and macrophages by dephosphorylating critical tyrosine kinases and signal transduction molecules. Because Y. pestis strains lacking YopH are avirulent, we set out to develop small molecule inhibitors for YopH. We used a novel and cost-effective approach, in which leads from a chemical library screening were analyzed and computationally docked into the crystal structure of YopH. This resulted in the identification of a series of novel YopH inhibitors with nanomolar K i values, as well as the structural basis for inhibition. Our inhibitors lack the polar phosphate-mimicking moiety of rationally designed tyrosine phosphatase inhibitors, and they readily entered live cells and rescued them from YopHinduced tyrosine dephosphorylation, signaling paralysis, and cell death. These inhibitors may become useful for treating the lethal infection by Y. pestis.

A Structure-based Approach to Retinoid X Receptor-α Inhibition

“…For these reasons, we tried to optimize the parameters for the scoring functions in a way that would emphasize the importance of hydrogen bonding interactions. By using in-house data from high throughput screening (30) and smaller scale screening projects (28,31,32), we scaled the parameters of the empirical terms of Chemscore (33) that produced the most reliable ranking ( Table 1). As internal control we used the x-ray-derived docked structure of the compound BMS-649 in complex with RXR␣ (Protein Data Bank code 1MVC) (17).…”

Wzy-Dependent Bacterial Capsules as Potential Drug Targets

“…These are mainly developed for the treatment of non-pathogenic diseases such as diabetes mellitus, cancer, and neural disorders. As potential drugs against pathogens, there has been some success in targeting PTPs in both Gram-positive and -negative organisms, for example Mycobacterium tuberculosis [102][103][104] and Yersinia pestis [105,106]. Although demonstrably viable as drug targets, and increasingly specific compounds are under development, there are as of yet no clinically approved PTP inhibitors available.…”

Development of Molecular Probes for Second-Site Screening and Design of Protein Tyrosine Phosphatase Inhibitors

“…Recent studies from our laboratories focused on the inhibition of the bacterial protein tyrosine phosphatase YopH [8]. Aided by a combination of chemical library screening, structureactivity relationships analysis and in silico docking of lead compounds, we developed smallmolecule inhibitors of YopH [8].…”

“…Aided by a combination of chemical library screening, structureactivity relationships analysis and in silico docking of lead compounds, we developed smallmolecule inhibitors of YopH [8]. Our inhibitors contain a single salicylate linked to a furanyl moiety as phosphotyrosine mimic and a more variable group that could be exploited to achieve selectivity and higher affinity [8]. In fact, while very small differences can be seen in the phosphotyrosine binding pockets of tyrosine phosphatases, unique sub-pockets can be found in adjacent regions [3,8].…”

“…Our inhibitors contain a single salicylate linked to a furanyl moiety as phosphotyrosine mimic and a more variable group that could be exploited to achieve selectivity and higher affinity [8]. In fact, while very small differences can be seen in the phosphotyrosine binding pockets of tyrosine phosphatases, unique sub-pockets can be found in adjacent regions [3,8]. Therefore, it appears evident that by tailoring a second-site ligand, it should be possible to develop potent and selective inhibitors of therapeutically relevant protein tyrosine phosphatases.…”