Potential peptidic proteasome inhibitors by incorporation of an electrophilic trap based on amino acid derived α-substituted sulfonyl fluorides

Peptido sulfonyl fluoride derivatives were designed and synthesized containing a substituent on the alpha position (αPSFs) with respect to the sulfonyl fluoride electrophilic trap. The chemical reactivity of these α-substituted amino sulfonyl fluorides was studied and compared with the previously described β-substituted amino sulfonyl fluorides in order to get a deeper insight into the importance of the immediate structural environment of the sulfonyl fluoride moiety. Unfortunately, the poor solubility of the resulting αPSFs precluded a proper evaluation of their biological activity

Proteasome inhibition by new dual warhead containing peptido vinyl sulfonyl fluorides

The success of inhibition of the proteasome by formation of covalent bonds is a major victory over the long held-view that this would lead to binding the wrong targets and undoubtedly lead to toxicity. Great challenges are now found in uncovering ensembles of new moieties capable of forming long lasting ties. We have introduced peptido sulfonyl fluorides for this purpose. Tuning the reactivity of this electrophilic trap may be crucial for modulating the biological action. Here we describe incorporation of a vinyl moiety into a peptido sulfonyl fluoride backbone, which should lead to a combined attack of the proteasome active site threonine on the double bond and the sulfonyl fluoride. Although this led to strong proteasome inhibitors, in vitro studies did not unambiguously demonstrate the formation of the proposed seven-membered ring structure. Possibly, formation of a seven-membered covalent adduct with the proteosomal active site threonine can only be achieved within the context of the enzyme. Nevertheless, this dual warhead concept may provide exclusive possibilities for duration and selectivity of proteasome inhibition

Immobilization by surface conjugation of cyclic peptides for effective mimicry of the HCV-envelope E2 protein as a strategy toward synthetic vaccines

Mimicry of the binding interface of antibody-antigen interactions using peptide-based modulators (i.e. epitope mimics) has promising applications for vaccine design. These epitope mimics can be synthesized in a streamlined and straightforward fashion, thereby allowing for high-throughput analysis. The design of epitope mimics is highly influenced by their spatial configuration and structural conformation. It is widely assumed that for proper mimicry sufficient conformational constraints have to be implemented. This paper describes the synthesis of bromide derivatives functional-ized with a flexible TEG linker equipped with a thiol-moiety that could be used to support cyclic or linear peptides. The cyclic and linear epitope mimics were covalently conjugated via the free thiol-moiety on maleimide-activated plate sur-faces. The resulting covalent, uniform, and oriented coated surface of cyclic or linear epitope mimics were subjected to an ELISA to investigate the effect of peptide cyclization with respect to mimicry of an antigen-antibody interaction of the HCV E2 glycoprotein. To our knowledge, the benefit of cyclized peptides over linear peptides has been clearly demon-strated here for the first time. Cyclic epitope mimics, and not the linear epitope mimics, demonstrated specificity towards their monoclonal antibodies HC84.1 and V3.2, respectively. The described strategy for the construction of epitope mimics shows potential for high-throughput screening of key-binding residues by simply changing the amino-acid sequences within synthetic peptides. In this way, leucine-438 has been identified as a key-binding residue for binding monoclonal antibody V3.2

Potent and highly selective inhibitors of the proteasome trypsin-like site by incorporation of basic side chain containing amino acid derived sulfonyl fluorides

A unique category of basic side chain containing amino acid derived sulfonyl fluorides (SFs) has been synthesized for incorporation into new proteasome inhibitors targeting the trypsin-like site of the 20S proteasome. Masking the former α-amino functionality of the amino acid starting derivatives as an azido functionality allowed an elegant conversion to the corresponding amino acid derived sulfonyl fluorides. The inclusion of different SFs at the P1 site of a proteasome inhibitor resulted in 14 different peptidosulfonyl fluorides (PSFs) having a high potency and an excellent selectivity for the proteolytic activity of the β2 subunit over that of the β5 subunit. The results of this study strongly indicate that a free N-terminus of PSFs inhibitors is crucial for high selectivity toward the trypsin-like site of the 20S proteasome. Nevertheless, all compounds are slightly more selective for inhibition of the constitutive over the immunoproteasome

Key Result Indicators (KRIS) and Key Performance Indicators (KPIS) For Maintenance Management

Maintenance management is an important process in the operation phase of any asset because it can impact the serviceability and useful life of the assets. In addition, maintenance management constitutes a substantial proportion of operational asset costs. Establishing a suitable set of (i) key result indicators to evaluate maintenance management and (ii) key performance indicators (KPIs) to improve maintenance decision making is essential for monitoring primary aspects of maintenance functions. While many KPIs have been defined for evaluating maintenance management and subsequently used for identifying root causes of deficiencies, there are potential areas for improvement in defining their relation with KRIs and supporting maintenance decisions. This paper aims to identify the KRIs and KPIs related to maintenance management by conducting a literature review and exploring the use of performance measures in maintenance management from organizational and algorithmic perspectives. The identified KRIs and KPIs are then analysed and categorised based on their purpose and content. In addition, primary data from interviews of industry practitioners is collected to identify the challenges of measuring maintenance performance in practice. The findings of this study show the lack of quality and reliable data, and automated data collection are the main issues in measuring KPIs for maintenance management. In addition, it was found that communication with the clients to understand their needs and update the KPIs based on their requirements and objectives over time could improve the effectiveness of the maintenance monitoring systems

The dissolution and microbial degradation of mobile aromatic hydrocarbons from a Pintsch gas tar DNAPL source zone

Source zones containing tar, a dense non-aqueous phase liquid (DNAPL), can contaminate groundwater for centuries. A common occurrence of tar is at former Pintsch gas factories. Little is known about the composition and fate of contaminants dissolving from Pintsch gas tar DNAPL. In this study, we determined the composition and water-soluble characteristics of mobile aromatic hydrocarbons and their biodegradation metabolites in the DNAPL contaminated groundwater at a former Pintsch gas tar plant. We assessed the factors that determine the fate of observed groundwater contaminants. Measured values of density (1.03–1.06 kg/m3) and viscosity (18.6–39.4 cP) were found to be relatively low compared to common coal tars. Analysis showed that unlike common coal tars phenanthrene is the primary component rather than naphthalene. Moreover, it was found that Pintsch gas tar contains a relatively high amount of light molecular aromatic hydrocarbon compounds, such as benzene, toluene, ethylbenzene and xylenes (BTEX). Less commonly reported components, such as styrene, ethyltoluenes, di-ethylbenzene, 1,2,4,5-tetramethylbenzene, were also detected in water extracts from Pintsch gas tar. Moreover, 46 relatively hydrophilic metabolites were found within the tar samples. Metabolites present within the tar suggest biodegradation of mobile aromatic Pintsch gas tar compounds occurred near the DNAPL. Based on eleven detected suspect metabolites, a novel anaerobic biodegradation pathway is proposed for indene. Overall, our findings indicate that Pintsch gas tar has higher invasive and higher flux properties than most coal tars due to its relatively low density, low viscosity and, high content of water-soluble compounds. The partitioning of contaminants from multi-component DNAPL into the aqueous phase and re-dissolution of their slightly less hydrophobic metabolites back from the aqueous phase into the DNAPL is feasible and demonstrates the complexity of assessing degradation processes within a source zone