Stephan M. Hacker

Leiden University

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Andreas Marx

University of Konstanz

Stephan A. Sieber

Technical University of Munich

Patrick R. A. Zanon

Scripps (United States)

Lisa Lewald

Technical University of Munich

Michael Zollo

Technical University of Munich

Martin Scheffner

University of Konstanz

Norman Hardt

Merck Serono (Switzerland)

Mathias W. Hackl

Technical University of Munich

Dario Mrdović

The University of Tokyo

F. Dean Toste

University of California, Berkeley

Cooperative Institutions

Technical University of Munich

Center for Integrated Protein Science Munich

University of Konstanz

Centre National de la Recherche Scientifique

Université de Toulouse

Université Toulouse III - Paul Sabatier

Leiden University

Scripps Research Institute

Ludwig-Maximilians-Universität München

Helmholtz Centre for Infection Research

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms

Nature Chemistry (2019)

Philipp Le Elena Kunold Robert Macsics Katharina Rox Megan C. Jennings

Drug repositioning

Efflux

Mode of Action

Pathogenic bacteria

10.1038/s41557-019-0378-7

Cite

Citations (113)

Development of Inhibitors, Probes, and PROTAC Provides a Complete Toolbox to Study PARK7 in the Living Cell

Journal of Medicinal Chemistry (2024)

Yuqing Jia Merve Oyken Robbert Q. Kim Rayman T.N. Tjokrodirijo Arnoud H. de Ru

The integration of diverse chemical tools like small-molecule inhibitors, activity-based probes (ABPs), and proteolysis targeting chimeras (PROTACs) advances clinical drug discovery and facilitates the exploration of various biological facets of targeted proteins. Here, we report the development of such a chemical toolbox for the human Parkinson disease protein 7 (PARK7/DJ-1) implicated in Parkinson's disease and cancers. By combining structure-guided design, miniaturized library synthesis, and high-throughput screening, we identified two potent compounds,

Toolbox

Drug Development

Human disease

Proteolysis

10.1021/acs.jmedchem.3c02410

Cite

Citations (1)

Publisher Correction: A proteome-wide atlas of lysine-reactive chemistry

Nature Chemistry (2021)

Mikail E. Abbasov Madeline E. Kavanagh Taka-Aki Ichu Michael R. Lazear Yongfeng Tao

Proteome

10.1038/s41557-021-00823-x

Cite

Citations (1)

Phosphate-Modified Nucleotides for Monitoring Enzyme Activity

Topics in current chemistry collections (2017)

Susanne Ermert Andreas Marx Stephan M. Hacker

Nucleobase

10.1007/978-3-319-60357-5_6

Cite

Citations (1)

Isotopically Labeled Desthiobiotin Azide (isoDTB) Tags Enable Global Profiling of the Bacterial Cysteinome

Patrick R. A. Zanon Lisa Lewald Stephan M. Hacker

Rapid development of bacterial resistance has led to an urgent need to find new druggable targets for antibiotics. In this context, residue-specific chemoproteomic approaches enable proteome-wide identification of binding sites for covalent inhibitors. Here, we describe isotopically labeled desthiobiotin azide (isoDTB) tags that are easily synthesized, shorten the chemoproteomic workflow and allow an increased coverage of cysteines in bacterial systems. We quantify 59% of all cysteines in essential proteins in <i>Staphylococcus aureus</i> and discover 88 cysteines with high reactivity, which correlates with functional importance. Furthermore, we identify 268 cysteines that are engaged by covalent ligands. We verify inhibition of HMG-CoA synthase, which will allow addressing the bacterial mevalonate pathway through a new target. Overall, a comprehensive map of the bacterial cysteinome is obtained, which will facilitate the development of antibiotics with novel modes-of-action.

Druggability

Proteome

10.26434/chemrxiv.9853445

Cite

Citations (0)

Light-Activatable, 2,5-Disubstituted Tetrazoles for the Proteome-Wide Profiling of Aspartates and Glutamates in Living Bacteria

Kathrin Bach Bert L. H. Beerkens Patrick R. A. Zanon Stephan M. Hacker

Covalent inhibitors have recently seen a resurgence of interest in drug development. Nevertheless, compounds, that do not rely on an enzymatic activity, have almost exclusively been developed to target cysteines. Expanding the scope to other amino acids would be largely facilitated by the ability to globally monitor their engagement by covalent inhibitors. Here, we present the use of light-activatable 2,5-disubstituted tetrazoles that allow quantifying 8971 aspartates and glutamates in the bacterial proteome with excellent selectivity. Using these probes, we competitively map the binding sites of two isoxazolium salts and introduce hydrazonyl chlorides as a new class of carboxylic acid-directed covalent protein ligands. As the probes are unreactive prior to activation, they allow global profiling even in living Gram-positive and Gram-negative bacteria. Taken together, this method to monitor aspartates and glutamates proteome-wide will lay the foundation to efficiently develop covalent inhibitors targeting these amino acids

Proteome

10.26434/chemrxiv.11352101

Cite

Citations (9)

Synthesis of γ‐Phosphate‐Labeled and Doubly Labeled Adenosine Triphosphate Analogs

Current Protocols in Nucleic Acid Chemistry (2015)

Stephan M. Hacker Moritz Welter Andreas Marx

Abstract This unit describes the synthesis of γ‐phosphate‐labeled and doubly labeled adenosine triphosphate (ATP) analogs and their characterization using the phosphodiesterase I from Crotalus adamanteus (snake venom phosphodiesterase; SVPD). In the key step of the synthesis, ATP or an ATP analog, bearing a linker containing a trifluoroacetamide group attached to the nucleoside, are modified with an azide‐containing linker at the terminal phosphate using an alkylation reaction. Subsequently, different labels are introduced to the linkers by transformation of one functional group to an amine and coupling to an N ‐hydroxysuccinimide ester. Specifically, the Staudinger reaction of the azide is employed as a straightforward means to obtain an amine in the presence of various labels. Furthermore, the fluorescence characteristics of a fluorogenic, doubly labeled ATP analog are investigated following enzymatic cleavage by SVPD. © 2015 by John Wiley & Sons, Inc.

Linker

Cleavage (geology)

Nucleoside triphosphate

Protecting group

Adenosine triphosphate

10.1002/0471142700.nc1314s60

Cite

Citations (2)

Author response for "The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21"

Esben B. Svenningsen Rasmus N. Ottosen Katrine H. Jørgensen Marija Nišavić Camilla K. Larsen

Basis (linear algebra)

Reactivity

10.1039/d2cb00161f/v2/response1

Cite

Citations (0)

Different Enzymatic Processing of γ-Phosphoramidate and γ-Phosphoester-Modified ATP Analogues

ChemBioChem (2016)

Susanne Ermert Stephan M. Hacker Alexander Buntru Martin Scheffner Christof R. Hauck

Monitoring the activity of ATP-consuming enzymes provides the basis for elucidating their modes of action and regulation. Although a number of ATP analogues have been developed for this, their scope is restricted because of the limited acceptance by respective enzymes. In order to clarify which kind of phosphate-modified ATP analogues are accepted by the α-β-phosphoanhydride-cleaving ubiquitin-activating enzyme 1 (UBA1) and the β-γ-phosphoanhydride-cleaving focal adhesion kinase (FAK), we tested phosphoramidate- and phosphoester-modified ATP analogues. UBA1 and FAK were able to convert phosphoramidate-modified ATP analogues, even with a bulky modification like biotin. In contrast, a phosphoester-modified analogue was poorly accepted. These results demonstrate that minor variations in the design of ATP analogues for monitoring ATP utilization have a significant impact on enzymatic acceptance.

Phosphodiester bond

Phosphoramidate

10.1002/cbic.201600590

Cite

Citations (6)

Monitoring enzymatic ATP hydrolysis by EPR spectroscopy

Chemical Communications (2014)

Stephan M. Hacker Christian Hintze Andreas Marx Malte Drescher

An adenosine triphosphate (ATP) analogue modified with two nitroxide radicals is developed and employed to study its enzymatic hydrolysis by electron paramagnetic resonance spectroscopy. For this application, we demonstrate that EPR holds the potential to complement fluorogenic substrate analogues in monitoring enzymatic activity.

Enzymatic Hydrolysis

10.1039/c4cc02422b

Cite

Citations (15)