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Hamburg, Germany

Hussain S.,Queen Mary, University of London | Khan A.,Queen Mary, University of London | Gul S.,Queen Mary, University of London | Gul S.,European Screening Port GmbH | And 4 more authors.
Biochemistry | Year: 2011

Understanding the roles of noncovalent interactions within the enzyme molecule and between enzyme and substrate or inhibitor is an essential goal of the investigation of active center chemistry and catalytic mechanism. Studies on members of the papain family of cysteine proteinases, particularly papain (EC itself, continue to contribute to this goal. The historic role of the catalytic site Cys/His ion pair now needs to be understood within the context of multiple dynamic phenomena. Movement of Trp177 may be necessary to expose His159 to solvent with consequent decrease in its degree of electrostatic solvation of (Cys25)-S -. Here we report an investigation of this possibility using computer modeling of quasi-transition states and pH-dependent kinetics using 3,3′-dipyridazinyl disulfide, its n-propyl and phenyl derivatives, and 4,4′-dipyrimidyl disulfide as reactivity probes that differ in the location of potential hydrogen-bonding acceptor atoms. Those interactions that influence ion pair geometry and thereby catalytic competence, including by transmission of the modulatory effect of a remote ionization with pK a 4, were identified. A key result is the correlation between the kinetic influence of the modulatory trigger of pK a 4 and disruption of the hydrogen bond donated by the indole N-H of Trp177, the hydrophobic shield of the initial "intimate" ion pair. This hydrogen bond is accepted by the amide O of Gln19-a component of the oxyanion hole that binds the tetrahedral species formed from the substrate during the catalytic act. The disruption would be expected to contribute to the mobility of Trp177 and possibly to the effectiveness of the binding of the developing oxyanion. © 2011 American Chemical Society.

Rosenkranz S.C.,University of Hamburg | Geissen M.,University of Hamburg | Harter K.,University of Hamburg | Szalay B.,University of Hamburg | And 4 more authors.
PLoS ONE | Year: 2013

Alzheimer's disease (AD) is the most common form of dementia in the elderly with progressive cognitive decline and memory loss. According to the amyloid-hypothesis, AD is caused by generation and subsequent cerebral deposition of β-amyloid (Aβ). Aβ is generated through sequential cleavage of the transmembrane Amyloid-Precursor-Protein (APP) by two endoproteinases termed beta- and gamma-secretase. Increased APP-expression caused by APP gene dosage effects is a risk factor for the development of AD. Here we carried out a large scale screen for novel compounds aimed at decreasing APP-expression. For this we developed a screening system employing a cell culture model of AD. A total of 10,000 substances selected for their ability of drug-likeness and chemical diversity were tested for their potential to decrease APP-expression resulting in reduced Aβ-levels. Positive compounds were further evaluated for their effect at lower concentrations, absence of cytotoxicity and specificity. The six most promising compounds were characterized and structure function relationships were established. The novel compounds presented here provide valuable information for the development of causal therapies for AD. © 2013 Rosenkranz et al.

Brandl B.,University of Kiel | Schneider S.A.,University of Kiel | Loring J.F.,Scripps Research Institute | Hardy J.,University College London | And 2 more authors.
Movement Disorders | Year: 2015

The introduction of stem cell-associated molecular factors into human patient-derived cells allows for their reprogramming in the laboratory environment. As a result, human induced pluripotent stem cells (hiPSC) can now be reprogrammed epigenetically without disruption of their overall genomic integrity. For patients with neurodegenerative diseases characterized by progressive loss of functional neurons, the ability to reprogram any individual's cells and drive their differentiation toward susceptible neuronal subtypes holds great promise. Apart from applications in regenerative medicine and cell replacement-based therapy, hiPSCs are increasingly used in preclinical research for establishing disease models and screening for drug toxicities. The rapid developments in this field prompted us to review recent progress toward the applications of stem cell technologies for movement disorders. We introduce reprogramming strategies and explain the critical steps in the differentiation of hiPSCs to clinical relevant subtypes of cells in the context of movement disorders. We summarize and discuss recent discoveries in this field, which, based on the rapidly expanding basic science literature as well as upcoming trends in personalized medicine, will strongly influence the future therapeutic options available to practitioners working with patients suffering from such disorders. © 2014 International Parkinson and Movement Disorder Society.

Mathas M.,University Hospital Freiburg | Nusshag C.,University Hospital Freiburg | Burk O.,Robert Bosch GmbH | Godtel-Armbrust U.,University Hospital Freiburg | And 4 more authors.
PLoS ONE | Year: 2014

The nuclear receptors and xenosensors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) induce the expression of xenobiotic metabolizing enzymes and transporters, which also affects various endobiotics. While human and mouse CAR feature a high basal activity and low induction upon ligand exposure, we recently identified two constitutive androstane receptors in Xenopus laevis (xlCARá and â) that possess PXR-like characteristics such as low basal activity and activation in response to structurally diverse compounds. Using a set of complementary computational and biochemical approaches we provide evidence for xlCARá being the structural and functional counterpart of mammalian PXR. A three-dimensional model of the xlCARá ligand-binding domain (LBD) reveals a human PXR-like L-shaped ligand binding pocket with a larger volume than the binding pockets in human and murine CAR. The shape and amino acid composition of the ligand-binding pocket of xlCAR suggests PXR-like binding of chemically diverse ligands which was confirmed by biochemical methods. Similarly to PXR, xlCARá possesses a flexible helix 11′. Modest increase in the recruitment of coactivator PGC-1á may contribute to the enhanced basal activity of three gain-of-function xlCARá mutants humanizing key LBD amino acid residues. xlCARá and PXR appear to constitute an example of convergent evolution. © 2014 Mathäs et al.

Bushman J.,New Jersey Center for Biomaterials | Mishra B.,University of Hamburg | Ezra M.,New Jersey Center for Biomaterials | Gul S.,European Screening Port GmbH | And 8 more authors.
Neuropharmacology | Year: 2014

Glycans attached to the cell surface via proteins or lipids or exposed in the extracellular matrix affect many cellular processes, including neuritogenesis, cell survival and migration, as well as synaptic activity and plasticity. These functions make glycans attractive molecules for stimulating repair of the injured nervous system. Yet, glycans are often difficult to synthesize or isolate and have the disadvantage to be unstable in a complex tissue environment. To circumvent these issues, we have screened a library of small organic compounds to search for structural and functional mimetics of the neurostimulatory glycan polysialic acid (PSA) and identified the 5-HT 4 receptor agonist tegaserod as a PSA mimetic. The PSA mimicking activity of tegaserod was shown in cultures of central and peripheral nervous system cells of the mouse and found to be independent of its described function as a serotonin (5-HT4) receptor agonist. In an in vivo model for peripheral nerve regeneration, mice receiving tegaserod at the site of injury showed enhanced recovery compared to control mice receiving vehicle control as evidenced by functional measurements and histology. These data indicate that tegaserod could be repurposed for treatment of nervous system injuries and underscores the potential of using small molecules as mimetics of neurostimulatory glycans. © 2013 Elsevier Inc. All rights reserved.

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