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Distribution by Scientific Domains

Chemistry	100%

Selected Abstracts

Inhibition of NF-,B activation with designed ankyrin-repeat proteins targeting the ubiquitin-binding/oligomerization domain of NEMO

PROTEIN SCIENCE, Issue 9 2007
Emanuel Wyler
Abstract The link between the NF-,B signal transduction pathway and cancer is now well established. Inhibiting this pathway is therefore a promising approach in the treatment of certain cancers through a pro-apoptotic effect in malignant cells. Owing to its central role in the pathway, the I,B kinase (IKK) complex is a privileged target for designing inhibitors. Previously, we showed that oligomerization of NEMO is necessary for IKK activation and defined a minimal oligomerization domain (CC2-LZ) for NEMO, and we developed NEMO peptides inhibiting NF-,B activation at the level of the IKK complex. To improve the low-affinity inhibitors, we used ribosome display to select small and stable proteins with high affinity against the individual CC2-LZ because the entire NEMO protein is poorly soluble. Several binders with affinities in the low nanomolar range were obtained. When expressed in human cells, some of the selected molecules, despite their partial degradation, inhibited TNF-,-mediated NF-,B activation while having no effect on the basal activity. Controls with a naive library member or null plasmid had no effect. Furthermore, we could show that this NF-,B inhibition occurs through a specific interaction between the binders and the endogenous NEMO, resulting in decreased IKK activation. These results indicate that in vitro selections with the NEMO subdomain alone as a target may be sufficient to lead to interesting compounds that are able to inhibit NF-,B activation. [source]

Application of a Library of Artificial Receptors Formed by Self-Organization of N -Lipidated Peptides Immobilized on Cellulose for Preliminary Studies of Binding of N -Phenylpiperazines

MOLECULAR INFORMATICS, Issue 6-7 2009
Justyna Fraczyk
Abstract A library of artificial receptors formed by self-organization of N -lipidated peptides attached to cellulose via aminophenylamino-1,3,5-triazine was synthesized and used for docking small, colorless guests. Interactions of colorless guest with receptors were visualized by using competitive adsorption-desorption of appropriate reporter dye. Analysis of binding pattern of N -phenylpiperazine derivatives with gradually increased lipophilicity was found diagnostic for structural changes of guest molecules. Several library members demonstrated attributes characteristic for detection of alteration of lipophilicity of the guest structure. [source]

Design and Synthesis of a Focused Library of Novel Aryl- and Heteroaryl-Ketopiperazides

ARCHIV DER PHARMAZIE, Issue 12 2004
Matthias Gerlach
Abstract 1-Phenyl-4-piperazinyl-carbonyl-substituted nitrogen-containing heterocycles were discovered at Zentaris as a new class of potent, synthetic, small molecule tubulin inhibitors with strong antiproliferative activity. The lead structure of this class, D-24203, proved to be a potent inhibitor of in vivo tumor growth in different xenograft models including mammary and renal cancers. As part of our efforts in the lead optimization process to expand structural diversity as well as to optimize bioavailability parameters such as solubility and metabolic stability for these compounds, we produced and evaluated a focused library containing 320 compounds. Five new heterocyclic compound classes with comparable activity properties in the cytotoxicity and tubulin polymerization assay could be identi fied. In silico calculated bioavailability parameters for selected library members provides new compound classes with improved solubility properties. Library design, development of adequate solution phase methodology, and synthesis will be presented, as well as results of lead optimization. [source]

Relating Chemical and Biological Diversity Space: A Tunable System for Efficient Gene Transfection

CHEMBIOCHEM, Issue 12 2008
Liisa D. Van Vliet Dr.
Abstract Polyethyleneimine (PEI), a well-established nonviral transfection reagent, was combinatorially modified with varying proportions of methyl, benzyl, and n -dodecyl groups to create a library of 435 derivatized polymers. Screening of this library for transfection, DNA binding, and toxicity allows systematic correlation of the biological properties of our polymers to their derivatizations. Combinations of derivatizations bring about a 100-fold variation in transfection efficiency between library members. The best PEI derivatives exhibit increases in transfection efficiency of more than 80-fold over unmodified PEI (up to 28±7,% of cells transfected) and rival commercial reagents such as Lipofectamine 2000 (21±10,%) and JetPEI (32±5.0,%). In addition, we can identify compounds that are specifically tuned for efficient transfection in CHO-K1 over Ishikawa cells and vice versa, demonstrating that the approach can lead to cell-type selectivity of at least one order of magnitude. This work demonstrates that multivalent derivatization of a polymeric framework can create functional diversity substantially greater than the structural diversity of the derivatization building blocks and suggests an approach to a better understanding of the molecular underpinnings of transfection as well as their exploitation. [source]

Evolution of a Constitutional Dynamic Library Driven by Self-Organisation of a Helically Folded Molecular Strand

CHEMISTRY - A EUROPEAN JOURNAL, Issue 16 2010
Lisa Lao Dr., Luciana
Abstract Conversion of macrocyclic imine entities into helical strands was achieved through three- and four-component exchange reactions within constitutionally dynamic libraries. The generation of sequences of the intrinsic helicity codon, based on the hydrazone,pyrimidine fragment obtained by condensation of pyrimidine dialdehyde A with pyrimidine bis-hydrazine B, shifted the equilibrium between all the possible macrocycles and strands towards the full expression (>98%) of helical product [A/B]. Furthermore, it was shown that chain folding accelerated the dynamic exchange reactions among the library members. Lastly, in four-component experiments (involving A, B, E and either C or D), even though the macrocyclic entities ([A/C], [B/E]; [A/D], [B/E]) were the kinetically preferred products, over time dialdehyde A relinquished its initial diamine partners C or D to opt for bis-hydrazine B, which allowed the preferential formation of the helically folded strand. The present results indicate that self-organisation pressure was able to drive the dynamic system towards the selective generation of the strand undergoing helical folding. [source]