Nicolas Winssinger

Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics

The war against infectious bacteria is not over! Although vancomycin and glycopeptide antibiotics have provided a strong last line of defence against many drug-resistant bacteria, their overuse has given rise to more dangerous strains of bacteria. An understanding of the chemistry and biology of these highly complex glycopeptides are destined to play a crucial role in the discovery of new antibiotics.

The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century.

A new millenium has begun-grounds enough to question the present state of the total synthesis of natural products. In this review we answer this question by tracing the evolution of this fine art and science from its birth to the present time. This retrospective on total synthesis should serve to demonstrate how far we have come, yet show that the science of total synthesis is still in its infancy.

Chemistry and biology of resorcylic acid lactones

While resorcylic acid lactones (RALs) have been known for a long time, the more recent discoveries that radicicol is a potent and selective HSP90 inhibitor while other members such as hypothemycin, LL-Z1640-2 and LL-783,277 are potent kinase inhibitors have stimulated a renewed interest in this family of natural products. The recent developments regarding the chemistry and biology of RALs are reviewed.

Profiling protein function with small molecule microarrays

The regulation of protein function through posttranslational modification, local environment, and protein–protein interaction is critical to cellular function. The ability to analyze on a genome-wide scale protein functional activity rather than changes in protein abundance or structure would provide important new insights into complex biological processes. Herein, we report the application of a spatially addressable small molecule microarray to an activity-based profile of proteases in crude cell lysates. The potential of this small molecule-based profiling technology is demonstrated by the detection of caspase activation upon induction of apoptosis, characterization of the activated caspase, and inhibition of the caspase-executed apoptotic phenotype using the small molecule inhibitor identified in the microarray-based profile.

Chemie, Biologie und medizinische Anwendungen der Glycopeptid‐Antibiotika

Der Krieg gegen pathogene Bakterien ist noch nicht vorbei! Zwar bilden Vancomycin und andere Glycopeptid-Antibiotika eine letzte Verteidigungslinie gegen zahlreiche mehrfachresistente Bakterien, doch ihr leichtfertiger Gebrauch hat zur Bildung etlicher gefahrlicherer Bakterienstamme gefuhrt. Das Verstandnis der chemischen und biologischen Eigenschaften dieser hochkomplexen Glycopeptide durfte eine entscheidende Rolle fur die Entdeckung und Entwicklung neuer Antibiotika spielen.

Imaging of mRNA in Live Cells Using Nucleic Acid-Templated Reduction of Azidorhodamine Probes

Nucleic acid-templated reactions leading to a fluorescent product represent an attractive strategy for the detection and imaging of cellular nucleic acids. Herein we report the use of a Staudinger reaction to promote the reduction of profluorescent azidorhodamine. The use of two cell-permeable GPNA probes, one labeled with the profluorescent azidorhodamine and the other with trialkylphosphine, enabled the detection of the mRNA encoding O-6-methylguanine-DNA methyltransferase in intact cells.

Target‐Accelerated Combinatorial Synthesis and Discovery of Highly Potent Antibiotics Effective Against Vancomycin‐Resistant Bacteria

Biological activity can be predicted at a prescreening stage by using a target-accelerated combinatorial synthesis. The rate of dimerization of vancomycin analogues (see picture, X=CH=CH2, SAc) in the presence of vancomycins targets Ac-d-Ala-d-Ala and Ac2-l-Lys-d-Ala-d-Ala correlated well with the observed biological activity. From this study three highly potent antibacterial agents effective against both vancomycin-susceptible and vancomycin-resistant bacteria strains were identified.

Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors.

Kinases have emerged as one of the most prolific therapeutic targets. An important criterion in the therapeutic success of inhibitors targeting the nucleotide binding pocket of kinases is the inhibitor residence time. Recently, covalent kinase inhibitors have attracted attention since they confer terminal inhibition and should thus be more effective than reversible inhibitors with transient inhibition. The most robust approach to design irreversible inhibitors is to capitalize on the nucleophilicity of a cysteine thiol group present in the target protein. Herein, we report a systematic analysis of cysteine residues present in the nucleotide binding site of kinases, which could be harnessed for irreversible inhibition, taking into consideration the different kinase conformations. We demonstrate the predictive power of this analysis with the design and validation of an irreversible inhibitor of KIT/PDGFR kinases. This is the first example of a covalent kinase inhibitor that combines a pharmacophore addressing the DFG-out conformation with a covalent trap.

Total Synthesis of Vancomycin

The fine-tuning of the protecting groups and the glycosidation conditions were the key to the successful coupling of the carbohydrate units and vancomycin aglycon in the last steps of the total synthesis of vancomycin 1. The aglycon was converted into a suitably protected acceptor and the sugar donors were sequentially attached. Removal of all the protecting groups gave synthetic vancomycin that was indentical to the natural product (1H and 13C NMR, HPLC).

Der Stand der Totalsynthese zu Beginn des 21. Jahrhunderts

Ein neues Jahrtausend hat begonnen – Grund genug, sich die Frage zu stellen, welchen Stand die Totalsynthese von Naturstoffen erreicht hat. Dieser Aufsatz mochte eine Antwort geben, indem er die Entwicklung dieser chemischen Disziplin, die Aspekte von exakter Wissenschaft und schoner Kunst in sich vereint, von Anbeginn bis in die heutige Zeit beschreibt; es wird geschildert, wie viel wir in der Wissenschaft der Totalsynthese schon erreicht haben, aber auch, dass dieses Forschungsgebiet den Kinderschuhen gerade erst entschlupft.