Search results for: Stephan A. Sieber

Items from 1 to 20 out of 92 results

article

Synthetic post‐translational modifications of elongation factor P using the ligase EpmA

Miriam Pfab, Pavel Kielkowski, Ralph Krafczyk, Wolfram Volkwein, more

Canonically, tRNA synthetases charge tRNA. However, the lysyl‐tRNA synthetase paralog EpmA catalyzes the attachment of (R)‐β‐lysine to the ε‐amino group of lysine 34 of the translation elongation factor P (EF‐P) in Escherichia coli. This modification is essential for EF‐P‐mediated translational rescue of ribosomes stalled at consecutive prolines. In this study, we determined the kinetics of EpmA and...

article

Total Synthesis of the Cyclic Depsipeptide Vioprolide D via its (Z)‐Diastereoisomer

Hanusch A. Grab, Volker C. Kirsch, Stephan A. Sieber, Thorsten Bach

Angewandte Chemie International Edition > 59 > 30 > 12357 - 12361

The first total synthesis of vioprolide D was accomplished in an overall yield of 2.0 % starting from methyl (2S)‐3‐benzyloxy‐2‐hydroxypropanoate (16 steps in the longest linear sequence). The cyclic depsipeptide was assembled from two building blocks of similar size and complexity in a modular, highly convergent approach. Peptide bond formation at the C‐terminal dehydrobutyrine amino acid of the...

article

Totalsynthese des cyclischen Depsipeptids Vioprolid D über sein (Z)‐Diastereomer

Hanusch A. Grab, Volker C. Kirsch, Stephan A. Sieber, Thorsten Bach

Angewandte Chemie > 132 > 30 > 12456 - 12460

Die erste Totalsynthese von Vioprolid D wurde ausgehend von (2S)‐3‐Benzyloxy‐2‐hydroxypropansäuremethylester in einer Gesamtausbeute von 2.0 % erreicht (16 Stufen in der längsten linearen Sequenz). Das cyclische Depsipeptid wurde aus zwei Bausteinen von ähnlicher Größe und Komplexität in einem modularen, hoch konvergenten Ansatz zusammengesetzt. Die Bildung einer Peptidbindung an der C‐terminalen...

article

Der zytotoxische Naturstoff Vioprolid A interagiert mit dem für die Ribosomen‐Biogenese essentiellen nukleolären Protein 14

Volker C. Kirsch, Christina Orgler, Simone Braig, Irmela Jeremias, more

Angewandte Chemie > 132 > 4 > 1611 - 1617

Für die Behandlung schwerer Krankheiten, wie z. B. Krebs, sind neue Angriffspunkte für die Therapie von großer Bedeutung. Seit Jahrzehnten treiben Naturstoffe die Entwicklung innovativer Therapieansätze voran, da diese in zellbiologische Prozesse eingreifen. Von der potenten zytotoxischen Aktivität der myxobakteriellen Vioprolide A–D inspiriert, wurden hier umfassende Studien bezüglich ihrer Wirkmechanismen...

article

The Cytotoxic Natural Product Vioprolide A Targets Nucleolar Protein 14, Which Is Essential for Ribosome Biogenesis

Volker C. Kirsch, Christina Orgler, Simone Braig, Irmela Jeremias, more

Angewandte Chemie International Edition > 59 > 4 > 1595 - 1600

Novel targets are needed for treatment of devastating diseases such as cancer. For decades, natural products have guided innovative therapies by addressing diverse pathways. Inspired by the potent cytotoxic bioactivity of myxobacterial vioprolides A–D, we performed in‐depth studies on their mode of action. Based on its prominent potency against human acute lymphoblastic leukemia (ALL) cells, we conducted...

article

A Chemical Proteomic Analysis of Illudin‐Interacting Proteins

Philipp Le, Matthew B. Nodwell, Jürgen Eirich, Stephan A. Sieber

Chemistry – A European Journal > 25 > 54 > 12644 - 12651

The illudin natural product family are fungal secondary metabolites with a characteristic spirocyclopropyl‐substituted fused 6,5‐bicyclic ring system. They have been extensively studied for their cytotoxicity in various tumor cell types, and semisynthetic derivatives with improved therapeutic characteristics have progressed to clinical trials. Although it is believed that this potent alkylating compound...

article

Polyamide/PEG Blends as Biocompatible Biomaterials for the Convenient Regulation of Cell Adhesion and Growth

Malte Winnacker, Andreas J. G. Beringer, Thomas F. Gronauer, Hicran H. Güngör, more

Macromolecular Rapid Communications > 40 > 12 > n/a - n/a

In addition to their established usage in textiles, commodities, and automotives, classical polyamides (nylons) are recently becoming increasingly interesting for applications in (bio)medicine. This fact relies on many prosperous properties of these polymers, which are toughness, resistance, biocompatibility, low immunogenicity, tunable biodegradability, and their similarity to natural peptides (amide...

article

Der Naturstoff Elegaphenon verstärkt antibiotische Effekte gegen Pseudomonas aeruginosa

Weining Zhao, Ashley R. Cross, Caillan Crowe‐McAuliffe, Angela Weigert‐Munoz, more

Angewandte Chemie > 131 > 25 > 8670 - 8674

Naturstoffe sind eine ergiebige Quelle für Antibiotika, die vielfältige zelluläre Zielstrukturen adressieren. Die Erforschung ihrer Zielproteine mittels chemischer Proteomik wird häufig durch das Einbringen sterisch anspruchsvoller photoreaktiver Gruppen erschwert. Hier verwenden wir Elegaphenon, ein weitestgehend uncharakterisiertes Naturstoffantibiotikum mit einem nativen Benzophenongrundgerüst...

article

The Natural Product Elegaphenone Potentiates Antibiotic Effects against Pseudomonas aeruginosa

Weining Zhao, Ashley R. Cross, Caillan Crowe‐McAuliffe, Angela Weigert‐Munoz, more

Angewandte Chemie International Edition > 58 > 25 > 8581 - 8584

Natural products represent a rich source of antibiotics that address versatile cellular targets. The deconvolution of their targets via chemical proteomics is often challenged by the introduction of large photocrosslinkers. Here we applied elegaphenone, a largely uncharacterized natural product antibiotic bearing a native benzophenone core scaffold, for affinity‐based protein profiling (AfBPP) in...

article

Tailored Peptide Phenyl Esters Block ClpXP Proteolysis by an Unusual Breakdown into a Heptamer–Hexamer Assembly

Markus Lakemeyer, Eva Bertosin, Friederike Möller, Dóra Balogh, more

Angewandte Chemie International Edition > 58 > 21 > 7127 - 7132

The proteolytic complex ClpXP is fundamental to bacterial homeostasis and pathogenesis. Because of its conformational flexibility, the development of potent ClpXP inhibitors is challenging, and novel tools to decipher its intricate regulation are urgently needed. Herein, we present amino acid based phenyl esters as molecular probes to study the activity and oligomerization of the ClpXP complex of...

article

Blockade der ClpXP‐vermittelten Proteolyse mit maßgeschneiderten Peptid‐Phenylestern durch den ungewöhnlichen Zerfall in eine Heptamer‐Hexamer‐Anordnung

Markus Lakemeyer, Eva Bertosin, Friederike Möller, Dóra Balogh, more

Angewandte Chemie > 131 > 21 > 7201 - 7206

Der proteolytische ClpXP‐Komplex ist essenziell für die bakterielle Homöostase und Pathogenese. Aufgrund seiner konformativen Flexibilität ist die Entwicklung wirksamer ClpXP‐Inhibitoren eine große Herausforderung, und neue Ansätze werden dringend benötigt, um die komplexe Enzymregulation zu verstehen. Aminosäurebasierte Phenylester werden hier als molekulare Sonden für die Untersuchung der Aktivität...

article

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

Markus Lakemeyer, Weining Zhao, Franziska A. Mandl, Peter Hammann, more

Angewandte Chemie > 130 > 44 > 14642 - 14682

Die öffentliche Wahrnehmung von Antibiotika als verlässliche Arzneimittel veränderte sich drastisch, als Meldungen über “multiresistente Super‐Erreger” die Nachrichten aufrüttelten. Während die Ursachen für die bakterielle Resistenzentwicklung schnell erkannt wurden, befindet sich die Forschung zur Wiedergewinnung von Antibiotika als effektive Arzneistoffe immer noch am Anfang. Dieser Aufsatz umfasst...

article

Selective Activation of Human Caseinolytic Protease P (ClpP)

Matthias Stahl, Vadim S. Korotkov, Dóra Balogh, Leonhard M. Kick, more

Angewandte Chemie International Edition > 57 > 44 > 14602 - 14607

Caseinolytic protease P (ClpP) is the proteolytic component of the ClpXP protein degradation complex. Eukaryotic ClpP was recently found to act within the mitochondria‐specific unfolded protein response (UPR^mt). However, its detailed function and dedicated regulation remain largely unexplored. A small molecule (D9) acts as a potent and species‐selective activator of human ClpP (hClpP) by mimicking...

article

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

Markus Lakemeyer, Weining Zhao, Franziska A. Mandl, Peter Hammann, more

Angewandte Chemie International Edition > 57 > 44 > 14440 - 14475

The public view on antibiotics as reliable medicines changed when reports about “resistant superbugs” appeared in the news. While reasons for this resistance development are easily spotted, solutions for re‐establishing effective antibiotics are still in their infancy. This Review encompasses several aspects of the antibiotic development pipeline from very early strategies to mature drugs. An interdisciplinary...

article

Selektive Aktivierung der humanen caseinolytischen Protease P (ClpP)

Matthias Stahl, Vadim S. Korotkov, Dóra Balogh, Leonhard M. Kick, more

Angewandte Chemie > 130 > 44 > 14811 - 14816

Die caseinolytische Protease P (ClpP) ist die proteolytische Komponente des Protein‐Abbau‐Komplexes ClpXP. Ihre genaue Funktion und Regulation sind größtenteils unerforscht. Hier stellen wir eine niedermolekulare Verbindung (D9) vor, die durch Nachahmung des natürlichen Chaperons ClpX als potenter und Spezies‐selektiver Aktivator der humanen ClpP (hClpP) wirkt. Struktur‐Aktivitäts‐Studien hoben die...

article

Ein antibakterielles β‐Lacton bekämpft Mycobacterium tuberculosis durch Infiltration der Mykolsäurebiosynthese

Johannes Lehmann, Tan‐Yun Cheng, Anup Aggarwal, Annie S. Park, more

Angewandte Chemie > 130 > 1 > 354 - 359

Eine der größten Herausforderungen für die Behandlung von Infektionen mit Mykobakterium tuberculosis ist Resistenzverbreitung. Des Weiteren ist die Aktivität vieler Wirkstoffe durch die limitierte Durchlässigkeit der Mykomembran eingeschränkt. Etablierte Antibiotika setzen daher auf die Lahmlegung der Mykomembranbiosynthese und führen zu einem schnellen Sterben der Zellen. Dieser Wirkmechanismus lieferte...

article

An Antibacterial β‐Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis

Johannes Lehmann, Tan‐Yun Cheng, Anup Aggarwal, Annie S. Park, more

Angewandte Chemie International Edition > 57 > 1 > 348 - 353

The spread of antibiotic resistance is a major challenge for the treatment of Mycobacterium tuberculosis infections. In addition, the efficacy of drugs is often limited by the restricted permeability of the mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis, leading to rapid cell death. Inspired by this mechanism, we exploited β‐lactones as putative mycolic acid mimics to block...

article

A Chemical Disruptor of the ClpX Chaperone Complex Attenuates the Virulence of Multidrug‐Resistant Staphylococcus aureus

Christian Fetzer, Vadim S. Korotkov, Robert Thänert, Kyu Myung Lee, more

Angewandte Chemie International Edition > 56 > 49 > 15746 - 15750

The Staphylococcus aureus ClpXP protease is an important regulator of cell homeostasis and virulence. We utilized a high‐throughput screen against the ClpXP complex and identified a specific inhibitor of the ClpX chaperone that disrupts its oligomeric state. Synthesis of 34 derivatives revealed that the molecular scaffold is restrictive for diversification, with only minor changes tolerated. Subsequent...

article

Verringerung der Virulenz von multiresistentem Staphylococcus aureus mithilfe eines chemischen Disruptors des ClpX‐Chaperon‐Komplexes

Christian Fetzer, Vadim S. Korotkov, Robert Thänert, Kyu Myung Lee, more

Angewandte Chemie > 129 > 49 > 15952 - 15957

Die ClpXP‐Protease von Staphylococcus aureus ist ein wichtiger Regulator der Zellhomöostase und Virulenz. Mithilfe eines Hochdurchsatz‐Screenings gegen den ClpXP‐Komplex wurde ein spezifischer Inhibitor des ClpX‐Chaperons identifiziert, der den oligomeren Zustand zerstört. Die Synthese von 34 Derivaten offenbarte, dass das molekulare Grundgerüst nur eingeschränkte Veränderungen ermöglicht und nur...

article

An amino acid domino effect orchestrates ClpP's conformational states

Matthias Stahl, Stephan A Sieber

Current Opinion in Chemical Biology > 2017 > 40 > C > 102-110

Maintaining the cellular protein homeostasis means managing life on the brink of death. This balance is largely based on precise fine-tuning of enzyme activities. For instance, the ClpP protease possesses several conformational switches which are fundamental to regulating its activity. Efforts have focused on revealing the structural basis of ClpP's conformational control. In the last decade, several...

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Search results for: Stephan A. Sieber

Synthetic post‐translational modifications of elongation factor P using the ligase EpmA

Total Synthesis of the Cyclic Depsipeptide Vioprolide D via its (Z)‐Diastereoisomer

Totalsynthese des cyclischen Depsipeptids Vioprolid D über sein (Z)‐Diastereomer

Der zytotoxische Naturstoff Vioprolid A interagiert mit dem für die Ribosomen‐Biogenese essentiellen nukleolären Protein 14

The Cytotoxic Natural Product Vioprolide A Targets Nucleolar Protein 14, Which Is Essential for Ribosome Biogenesis

A Chemical Proteomic Analysis of Illudin‐Interacting Proteins

Polyamide/PEG Blends as Biocompatible Biomaterials for the Convenient Regulation of Cell Adhesion and Growth

Der Naturstoff Elegaphenon verstärkt antibiotische Effekte gegen Pseudomonas aeruginosa

The Natural Product Elegaphenone Potentiates Antibiotic Effects against Pseudomonas aeruginosa

Tailored Peptide Phenyl Esters Block ClpXP Proteolysis by an Unusual Breakdown into a Heptamer–Hexamer Assembly

Blockade der ClpXP‐vermittelten Proteolyse mit maßgeschneiderten Peptid‐Phenylestern durch den ungewöhnlichen Zerfall in eine Heptamer‐Hexamer‐Anordnung

Über bisherige Denkweisen hinaus – neue Wirkstoffe zur Überwindung der Antibiotika‐Krise

Selective Activation of Human Caseinolytic Protease P (ClpP)

Thinking Outside the Box—Novel Antibacterials To Tackle the Resistance Crisis

Selektive Aktivierung der humanen caseinolytischen Protease P (ClpP)

Ein antibakterielles β‐Lacton bekämpft Mycobacterium tuberculosis durch Infiltration der Mykolsäurebiosynthese

An Antibacterial β‐Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis

A Chemical Disruptor of the ClpX Chaperone Complex Attenuates the Virulence of Multidrug‐Resistant Staphylococcus aureus

Verringerung der Virulenz von multiresistentem Staphylococcus aureus mithilfe eines chemischen Disruptors des ClpX‐Chaperon‐Komplexes

An amino acid domino effect orchestrates ClpP's conformational states

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