Philipp Beck

Universitätsklinikum Erlangen

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M. Groll

Technical University of Munich

F. Quitterer

Technical University of Munich

A. Bacher

Technical University of Munich

Andreas B. Wild

Universitätsklinikum Erlangen

Alexander Steinkasserer

Friedrich-Alexander-Universität Erlangen-Nürnberg

Christina Draßner

Universitätsklinikum Erlangen

Adelbert Bacher

Technical University of Munich

Christine Kuhnt

Universitätsklinikum Erlangen

Stefan Schliep

Friedrich-Alexander-Universität Erlangen-Nürnberg

Martin Stein

Technical University of Munich

Cooperative Institutions

Technical University of Munich

Universitätsklinikum Erlangen

Friedrich-Alexander-Universität Erlangen-Nürnberg

Ludwig-Maximilians-Universität München

Center for Integrated Protein Science Munich

Universität Ulm

LMU Klinikum

Charité - Universitätsmedizin Berlin

Freie Universität Berlin

Heidelberg University

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Soluble CD83 modulates human-monocyte-derived macrophages toward alternative phenotype, function, and metabolism

Frontiers in Immunology (2023)

Katrin Peckert-Maier Andreas B. Wild Laura Sprißler Maximilian Fuchs Philipp Beck

Alterations in macrophage (Mφ) polarization, function, and metabolic signature can foster development of chronic diseases, such as autoimmunity or fibrotic tissue remodeling. Thus, identification of novel therapeutic agents that modulate human Mφ biology is crucial for treatment of such conditions. Herein, we demonstrate that the soluble CD83 (sCD83) protein induces pro-resolving features in human monocyte-derived Mφ biology. We show that sCD83 strikingly increases the expression of inhibitory molecules including ILT-2 (immunoglobulin-like transcript 2), ILT-4, ILT-5, and CD163, whereas activation markers, such as MHC-II and MSR-1, were significantly downregulated. This goes along with a decreased capacity to stimulate alloreactive T cells in mixed lymphocyte reaction (MLR) assays. Bulk RNA sequencing and pathway analyses revealed that sCD83 downregulates pathways associated with pro-inflammatory, classically activated Mφ (CAM) differentiation including HIF-1A, IL-6, and cytokine storm, whereas pathways related to alternative Mφ activation and liver X receptor were significantly induced. By using the LXR pathway antagonist GSK2033, we show that transcription of specific genes (e.g., PPARG , ABCA1 , ABCG1 , CD36 ) induced by sCD83 is dependent on LXR activation. In summary, we herein reveal for the first time mechanistic insights into the modulation of human Mφ biology by sCD83, which is a further crucial preclinical study for the establishment of sCD83 as a new therapeutical agent to treat inflammatory conditions.

ABCG1

CD163

CD36

10.3389/fimmu.2023.1293828

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Citations (1)

Identifizierung eines Sulfonamids als β1/β2‐spezifischer Proteasomligand durch kristallographisches Screening

Angewandte Chemie (2015)

Philipp Beck Michèle Reboud‐Ravaux M. Groll

Abstract Das Proteasom ist ein etabliertes Angriffsziel zur Behandlung von Krebs, jedoch erfordert das Aufkommen resistenter Tumore die Entdeckung neuartiger Inhibitoren. Die häufig genutzten fluoreszenzbasierten Screeningmethoden besitzen jedoch eine geringe Empfindlichkeit und sind auf den Nachweis von Liganden mit koventionellen Bindungsprofilen begrenzt. Aufgrund dieser Nachteile haben wir ein kristallographisches Screeningverfahren angewendet, um Proteasominhibitoren mit einem neuartigen Wirkmechanismus zu identifizieren. Die optimierte Prozedur wurde anhand eines Screenings einer fokussierten Gruppe von Verbindungen getestet und führte zur Entdeckung eines β1/β2‐spezifischen Sulfonamid‐Derivats, das nicht‐kovalent zwischen den Proteasomuntereinheiten β1 und β2 bindet. Die Bindetasche zeigt signifikante Größen‐ und Polaritätsunterschiede zwischen konstitutivem und Immunproteasom auf, wodurch der identifizierte Ligand wertvolle Erkenntnisse für die strukturbasierte Entwicklung von Subtyp‐spezifischen Proteasominhibitoren bietet.

10.1002/ange.201505054

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Citations (3)

PylC in complex with L-lysine-Ne-D-ornithine (cocrystallized with L-lysine and D-ornithine)

F. Quitterer A. List Philipp Beck A. Bacher M. Groll

10.2210/pdb4ffm/pdb

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NOTCH1 Mutation and Treatment Outcome In CLL Patients Treated With Chlorambucil (Chl) Or Ofatumumab-Chl (O-Chl): Results From The Phase III Study Complement 1 (OMB110911)

Blood (2013)

Eugen Tausch Philipp Beck Richard F. Schlenk Sabrina Kless Christina Galler

IGHV@

Sanger sequencing

10.1182/blood.v122.21.527.527

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Ein systematischer Vergleich peptidischer Proteasominhibitoren unterstreicht α‐Ketoamid als vielversprechende elektrophile Leitstruktur

Angewandte Chemie (2014)

Martin Stein Haissi Cui Philipp Beck Christian Dubiella Constantin Voss

Abstract Das Ubiquitin‐Proteasom‐System (UPS) wurde in akademischer wie pharmazeutischer Forschung erfolgreich für onkologische und immunologische Anwendungen adressiert. Typische Proteasominhibitoren basieren auf einem peptidischen Rückgrat, das mit einem elektrophilen C‐Terminus zur Bindung an die aktiven proteolytischen Zentren gekuppelt ist. Obwohl der peptidische Anteil viel Interesse bezüglich der Untereinheitenselektivität hervorgerufen hat, wird die Wirkspezifität und biologische Stabilität der Substanzen entscheidend durch die reaktiven Kopfgruppen geprägt. In dieser Studie wurde daher eine systematische Untersuchung mit In‐vitro‐, In‐vivo‐ und strukturbiologischen Methoden durchgeführt, um die Auswirkungen unterschiedlicher Funktionalitäten und chemischer Reaktivitäten aufzudecken. Dies ermöglichte die Einführung und Charakterisierung der Klasse der α‐Ketoamide als potenteste reversible Inhibitoren mit möglichen Anwendungen für die Behandlung von soliden Tumoren und Autoimmunerkrankungen.

10.1002/ange.201308984

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Citations (22)

One-shot NMR analysis of microbial secretions identifies highly potent proteasome inhibitor

Proceedings of the National Academy of Sciences (2012)

Martin Stein Philipp Beck Markus Kaiser Robert Dudler Christian F. W. Becker

Natural products represent valuable lead structures for drug discovery. However, for most bioactive compounds no cellular target is yet identified and many substances predicted from genome analysis are inaccessible due to their life stage-dependent biosynthesis, which is not reflected in common isolation procedures. In response to these issues, an NMR-based and target-directed protease assay for inhibitor detection of the proteasome was developed. The methodology is suitable for one-shot identification of inhibitors in conglomerates and crude culture broths. The technique was applied for analysis of the different life stages of the bacterium Photorhabdus luminescens , which resulted in the isolation and characterization of cepafungin I (CepI), the strongest proteasome inhibitor described to date. Its biosynthesis is strictly regulated and solely induced by the specific environmental conditions determined by our methodology. The transferability of the developed technique to other drug targets may disclose an abundance of novel compounds applicable for drug development.

Drug Development

Isolation

Photorhabdus luminescens

10.1073/pnas.1211423109

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Citations (58)

Yeast 20S proteasome in Complex with Kendomycin

Philipp Beck W. Heinemeyer A. Spaeth Yasser A. Elnakady R. Mueller

10.2210/pdb4q1s/pdb

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PylD cocrystallized with L-Ornithine-Nd-D-ornithine and NAD+

F. Quitterer Philipp Beck A. Bacher M. Groll

10.2210/pdb4q3d/pdb

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α‐Keto Phenylamides as P1′‐Extended Proteasome Inhibitors

ChemMedChem (2014)

Constantin Voss Christoph Scholz Sabine Knorr Philipp Beck Martin Stein

Abstract The major challenge for proteasome inhibitor design lies in achieving high selectivity for, and activity against, the target, which requires specific interactions with the active site. Novel ligands aim to overcome off‐target‐related side effects such as peripheral neuropathy, which is frequently observed in cancer patients treated with the FDA‐approved proteasome inhibitors bortezomib ( 1 ) or carfilzomib ( 2 ). A systematic comparison of electrophilic headgroups recently identified the class of α‐keto amides as promising for next generation drug development. On the basis of crystallographic knowledge, we were able to develop a structure–activity relationship (SAR)‐based approach for rational ligand design using an electronic parameter (Hammett’s σ ) and in silico molecular modeling. This resulted in the tripeptidic α‐keto phenylamide BSc4999 [( S )‐3‐(benzyloxycarbonyl‐( S )‐leucyl‐( S )‐leucylamino)‐5‐methyl‐2‐oxo‐ N ‐(2,4‐dimethylphenyl)hexanamide, 6 a ], a highly potent (IC 50 =38 n M ), cell‐permeable, and slowly reversible covalent inhibitor which targets both the primed and non‐primed sites of the proteasome’s substrate binding channel as a special criterion for selectivity. The improved inhibition potency and selectivity of this new α‐keto phenylamide makes it a promising candidate for targeting a wider range of tumor subtypes than commercially available proteasome inhibitors and presents a new candidate for future studies.

Rational design

Ligand efficiency

10.1002/cmdc.201402244

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Citations (14)

Identification of a β1/β2‐Specific Sulfonamide Proteasome Ligand by Crystallographic Screening

Angewandte Chemie International Edition (2015)

Philipp Beck Michèle Reboud‐Ravaux M. Groll

Abstract The proteasome represents a validated drug target for the treatment of cancer, however, new types of inhibitors are required to tackle the development of resistant tumors. Current fluorescence‐based screening methods suffer from low sensitivity and are limited to the detection of ligands with conventional binding profiles. In response to these drawbacks, a crystallographic screening procedure for the discovery of agents with a novel mode of action was utilized. The optimized workflow was applied to the screening of a focused set of compounds, resulting in the discovery of a β1/β2‐specific sulfonamide derivative that noncovalently binds between subunits β1 and β2. The binding pocket displays significant differences in size and polarity between the immuno‐ and constitutive proteasome. The identified ligand thus provides valuable insights for the future structure‐based design of subtype‐specific proteasome inhibitors.

Sulfonamide

Mode of Action

10.1002/anie.201505054

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Citations (12)