Abstracts e1-e11 higuchi yeast infection pain biosciences center

The development of chemically unique electrophilic probes capable of modulating yeast infection pain biological nucleophiles is the focal point of this project. Toward this goal, an intramolecular C-vinylation method for the generation of electrophilic triazole-fused sultams is reported. This efficient method has enabled the synthesis of a small yeast infection pain library of diverse sultams. The electrophilic character of these sultams has been studied using yeast infection pain a variety of small nucleophiles, whereby scaffold reactivity screening, in combination with the reported method, is guiding efforts in second-generation probe design.

Currently it takes days to determine if a patient has yeast infection pain a bacterial infection, frequently leaving patients to be sent home with antibiotics before yeast infection pain their test results are in. Over prescribing of unneeded antibiotics contributes to the growing epidemic yeast infection pain of antibiotic resistant bacterium and could be avoided if there yeast infection pain was a method to detect bacterial infections quickly. Lipopolysaccharides (LPS) are bacterial endotoxins unique to outer membranes of gram-negative bacteria and are an important target for quicker detection yeast infection pain of pathogens. An LPS binding motif was identified from a crystal structure yeast infection pain of an E. Coli beta-barrel protein (fhua) bound with LPS. As beta-barrel proteins are difficult to purify and manipulate, an alpha-helical peptide was computationally designed to mimic the LPS binding yeast infection pain motif using preexisting helical templates and G-losa. Fluorescence anisotropy was used to probe the binding capabilities of yeast infection pain the designed peptide with escherichia coli, salmonella enterica, pseudomonas aeruginosa, and klebsiella pneumoniae LPS. Polymyxin B is an antibiotic known to bind to LPS yeast infection pain and was used as a positive control in the binding yeast infection pain assay by labeling it two different fluorophores. The designed peptide was found to bind the four types yeast infection pain of LPS with greater affinity than polymyxin B, with three of the four LPS samples binding to the yeast infection pain peptide with approximately an order of magnitude greater affinity.

Efforts towards an efficient, pot-economical asymmetric total synthesis of (–)-13-desmethyl-lyngbouilloside, an unnatural analog of lyngbouilloside (anticancer activity) will be discussed. The key reactions involved in the syntheses of (–)-13-desmethyl-lyngbouilloside are one-pot sequential RCM/CM/chemoselective hydrogenation, regio- and diastereoselective cuprate addition, a one-pot pd-catalyzed reductive allylic transposition, roskamp homologation and boeckman acyl-ketene cyclization to form the macrocyclic core of the target yeast infection pain molecule. This efficient, pot-economical and library amenable approach is further extended for the yeast infection pain syntheses of diverse and structurally related analog library of (–)-lyngbouilloside and (+)-neopeltolide. An iterative regio- and diastereoselective cuprate addition and late stage alcohol functionalization followed yeast infection pain by RCM/deprotection sequence enables the syntheses of a diverse range of yeast infection pain sterically, electronically and stereochemically attenuated macrocycles containing carbon-, sulfur- and phosphorus warheads. These analogs will be submitted to our collaborators for biological yeast infection pain screening.

Covalent modulators of cysteine residues have emerged as regulators of yeast infection pain protein function, including ubiquitination, sumoylation, prenylation, farnesylation, phosphorylation and glycosylation to name a few. In this regard, we report the synthesis of structurally diverse electrophilic sultam scaffolds yeast infection pain as modulators of cysteine functionality. Employing 19F NMR analyses, their reactivity profiling with N-acetyl cysteine was examined through kinetic measurements. It was demonstrated that their reactivity with cysteine is highly yeast infection pain dependant on the electronic effect, steric hindrance, as well as resident stereochemistry of the exo acetyl sultam yeast infection pain scaffolds.

Development of an efficient, step and pot-economical approach for the synthesis of a library of bi- and tricyclic phosphorus heterocyles is reported. Phosphorus heterocycles have been shown to impart a wide variety yeast infection pain of biological activities leading them to serve as novel pharmaceutical yeast infection pain agents and biological probes. The key reactions involved in the synthesis of these small yeast infection pain molecules include one-pot sequential, enyne ring-closing metathesis and diels-alder reaction (ERCM/DA). This step economical protocol enables access to structurally and stereochemically yeast infection pain diverse bi- and tricyclic phosphate and phosphoramidate analogs in fewer number of yeast infection pain steps from easily accessible precursors.

The university of kansas computational chemical biology core (CCB) provides the computational resources and expertise to enhance the productivity yeast infection pain of researchers studying infectious diseases. The CCB is able to provide or assist with virtual yeast infection pain screening, protein-small molecule docking, binding site prediction, protein modeling and design, prediction of protein stability changes upon mutation, fragment based probe design, as well as preparation of presentation graphics. The core utilizes the KU community cluster at the advanced yeast infection pain computing facility for its high-performance computing needs. The KU community cluster offers 458 compute nodes with a yeast infection pain total of 8,568 compute cores, including 17 nodes that offer GPU-accelerated computing. The CCB specializes in initial hit identification of non-traditional drug targets such as protein-protein or protein-RNA interfaces by offering high-throughput virtual screening via pocket optimization with exemplar screening at yeast infection pain protein-protein interfaces and hotspot pharmacophore mimicry of protein-RNA interactions.

Systematic studies of the role of thiol (or cysteine)-containing amino acids and peptides in many physiological processes have yeast infection pain emerged. In particular, modification of thiol (or cysteine)-containing amino acids via michael addition reactions have surfaced as yeast infection pain modification of the ERK, nrf2, and NF-kb biological pathways, as well as a potential cure for the parasitic disease yeast infection pain known as chagas disease. Thus, rapid, sensitive, and selective detection of regulatory thiols is of considerable importance yeast infection pain and significant interest in the development of small-molecule electrophilic probes and drugs. Analysis of thiol reactivity under various conditions utilizing 19F NMR yeast infection pain has allowed us to optimize thiol addition reactions to previously yeast infection pain synthesized exo/endo vinyl sultams, vinyl β-keto sultam analogs of tetramic acids, as well as sulfonamides and known drugs, including antitumor and antifungal agents. Efficient catalytic reactions governed by arginine and histidine to increase yeast infection pain thiol- and cysteine-michael addition reactivity will also be discussed. For future work, all compounds will be screened to reveal biological activity and yeast infection pain to provide a better understanding of biochemistry in health and yeast infection pain disease.

The diffusion of small peptides across a lipid membrane was yeast infection pain determined, characterized, and compared to experimental values by using molecular dynamics simulations. Blocked phenylalanine, tyrosine, tryptophan, and wh5a were studied. The lipid membrane was constructed by using 50 DOPC lipids yeast infection pain surrounded by around 3000 water molecules. The simulations were setup by using CHARMM and then run yeast infection pain with the GROMACS program. Potentials of mean force indicated preferential binding of the peptides yeast infection pain to the lipid interface and large free energy barriers at yeast infection pain the membrane center. Peptide translational diffusion rates show small changes between solution, interface and membrane interior. In contrast, the sidechain rotational correlation times show extremely large changes with yeast infection pain membrane insertion, with values becoming 100 time greater in the head-group region and 10 times greater in the tail region, compared to solution. The peptides’ conformational freedom becomes systematically more restricted as they enter the yeast infection pain membrane, sampling α, β and C 7eq conformers in solution and only C yeast infection pain 7eq in the center. Differences between system size, 40 or 50 lipids, and lipid type, DOPC or POPC, were also examined and indicate little or no change of yeast infection pain properties.

Surface properties of biocompatible scaffolds can be easily modified using yeast infection pain bioactive molecules to control stem cell differentiation into the osteogenic yeast infection pain lineage. An innovative solution is the use of a polydopamine coating yeast infection pain as linking strategy to bind signal molecules capable of directing yeast infection pain stem cell behavior. In this study, a gelatin-alginate interpenetrated network (IPN) was fabricated using different amounts of N-hydroxysuccinimide (NHS), and ethyl carbodiimide (EDC) as crosslinkers to produce tunable scaffolds for human adipose mesenchymal yeast infection pain stem cell (hascs) differentiation into the bone lineage. High and low crosslinked hydrogels were obtained and characterized by yeast infection pain their ability to swell, degrade and resist different mechanical stimuli. In addition, the surface of the scaffolds was coated with polydopamine as yeast infection pain a bonding layer for bioactive molecules to promote hascs differentiation. Results showed a higher absorption of dexamethasone could be achieved yeast infection pain using a polydopamine coating respect to the uncoated hydrogels. As expected, hascs cultured on the scaffold coated with polydopamine and dexamethasone yeast infection pain showed significantly higher differentiation markers such as alkaline phosphatase and yeast infection pain higher calcium deposition when compared to the control groups. Due to these promising findings, this scaffold could be potentially used as an osteoinductive coating yeast infection pain for biomedical implants to enhance bone regeneration.

The synthetic chemical biology core strives to provide comprehensive synthetic yeast infection pain chemistry capabilities to investigators under one roof. The synthetic expertise of the core includes, but is not limited to, novel and commercially unavailable small molecules, fluorescent molecules and peptides. The core assists in identifying hits for medicinal chemistry optimization yeast infection pain in infectious disease targets and provides synthesis capabilities for structure yeast infection pain activity studies of said hits. The core staff will work with investigators to design and yeast infection pain synthesis novel molecular probes to facilitate their research. SCB core additionally provides access to the model organism danio yeast infection pain rerio (zebrafish), and allows investigators to image embryonic and adult zebrafish treated yeast infection pain with molecular probes for phenotypic drug discovery and other projects. SCB core encompasses the purification and analysis laboratory (PAL) that provides purification, analysis and quality control of compounds via HPLC-MS. The core utilizes automated mass directed fractionation for purification in yeast infection pain both reversed and normal phases (including chiral separations), and also provides relative purity analysis by UPLC coupled to yeast infection pain a high-resolution mass spectrometer for structure confirmation.

1 deparment of chemistry, university of kansas, lawrence, KS, USA; 2department of chemistry and biochemistry, wilfrid laurier university, waterloo, ON, canada; 3department of chemistry, department of biochemistry and molecular biology, pennsylvania state university, state college, PA, USA; 4howard hughes medical institute, chevy chase, MD, USA; 5department of medicinal chemistry, university of kansas, lawrence, KS, USA; 6department of molecular biosciences, university of kansas, lawrence, KS, USA

Nonribosomal peptide synthetases (nrpss) are one approach used by microbes to generate bioactive peptides. These bioactive peptides are not only used as secondary metabolites yeast infection pain (toxins, pigments, siderophores – iron scavenging molecules), but have found their way into the clinic as antibiotics, anticancer drugs, and immunosuppressants. To elicit their unique bioactivity, these peptides must be tailored. Natural product chemists, metabolic engineers, and researchers in biochemistry and biotechnology work to exploit the yeast infection pain biosynthesis of these secondary metabolites in order to generate new yeast infection pain compounds for clinical use. The long term goal of this project is to understand yeast infection pain the structure-function relationships of epimerases and methyltransferases that are incorporated into yeast infection pain these assembly lines. Structural biology and mechanistic enzymology can provide novel insight and yeast infection pain assist natural product investigations, protein engineering projects, antimicrobial development, and other therapeutic design. Currently there is no adenylation-tailoring “stuffed” didomain NRPS structures, and limited biochemical characterization exists. This project concentrates on the adenylation-epimerase didomain of pche and the adenylation-methyltransferase didomain of pchf in the biosynthetic pathway of the yeast infection pain siderophore, pyochelin. Initial work includes substrate analogue synthesis and the establishment of yeast infection pain adenylation, epimerization, and methyltransferase assays.

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