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Many modern drugs were discovered using high-throughput phenotypic screening approaches. Historically, the subsequent identification of cellular targets of the screening hits has been cumbersome and inconsistent, thus holding back their development into promising drug candidates. Recent progress in mass spectrometry-based chemoproteomics, a highly interdisciplinary and rapidly emerging research area my laboratory is specialized in, made the target identification step much more manageable. Chemical probes and their cellular targets discovered by chemoproteomics can be used to investigate the disease involvement of certain biological pathways and concomitantly serve as leads for clinical drug development.
Broadly speaking, my laboratory is working at the interface of synthetic chemistry, biochemistry and proteomics. We seek to develop chemical tools and mass spectrometry-based platforms for chemoproteomics-enabled target identification and drug discovery with a specific focus on proteins of high therapeutic promise that are currently considered “undruggable“.
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A. Chemoproteomic probe and method development
We are developing new chemoproteomic probes and platforms for target identification. We are particularly interested in hypervalent iodine-based reagents and their application as bioorthogonal chemoproteomic probes.
- Proteome-Wide Profiling of Targets of Cysteine-reactive Small Molecules by using Ethynyl Benziodoxolone Reagents
Daniel Abegg, Reto Frei, Luca Cerato, Durga Prasad Hari, Chao Wang, Jerome Waser, Alexander Adibekian*
Angew. Chem. Int. Ed. 2015, 54, 10852-10857
- Ethynylation of Cysteines from Peptides to Proteins in Living Cells
Romain Tessier, Raj Kumar Nandi, Brendan G. Dwyer, Daniel Abegg, Charlotte Sornay, Javier Ceballos, Stephane Erb, Sarah Cianferani, Alain Wagner, Guilhem Chaubet*, Alexander Adibekian*, Jerome Waser*
Angew. Chem. Int. Ed. 2020, 59, 10961-10970
- Chemoproteomic Profiling by Cysteine Fluoroalkylation Reveals Myrocin G as an Inhibitor of the Nonhomologous End Joining DNA Repair Pathway
Daniel Abegg, Martin Tomanik, Nan Qiu, Dany Pechalrieu, Anton Shuster, Bruno Commare, Antonio Togni, Seth B. Herzon, Alexander Adibekian*
J. Am. Chem. Soc. 2021, 143, 20332-20342
B. Natural product target identification
We are applying our probes and methods to identify and biochemically characterize the molecular targets of natural products with intriguing bioactivities with the goal of understanding their molecular mechanism of action.
- Total Synthesis and Target Identification of the Curcusone Diterpenes
Chengsen Cui,# Brendan G. Dwyer,# Chang Liu, Daniel Abegg, Zhong-Jian Cai, Dominic G. Hoch, Xianglin Yin, Nan Qiu, Jie-Qing Liu, Alexander Adibekian*, Mingji Dai*
J. Am. Chem. Soc. 2021, 143, 4379-4386
- Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6
Nan Qiu, Daniel Abegg, Mara Guidi, Kerry Gilmore, Peter H. Seeberger, Alexander Adibekian*
Cell Chem. Biol. 2022, 29, 539-537
- Comprehensive Structure–Activity Relationship Studies of Cepafungin Enabled by Biocatalytic C–H Oxidations
Alexander Amatuni, Anton Shuster, Daniel Abegg, Alexander Adibekian*, Hans Renata*
ACS Cent. Sci. 2023, 9, 239-251
C. Chemoproteomics-enabled drug discovery
We are evolving novel synthetic routes that allow rapid access to structurally diverse collections of small molecules, screen these small molecules in various disease models of interest, and identify their targets using our in-house chemoproteomic profiling methods.
- Chemoproteomics-Enabled Discovery of a Potent and Selective Inhibitor of the DNA-Repair Protein MGMT
Chao Wang,# Daniel Abegg,# Dominic G. Hoch, Alexander Adibekian*
Angew. Chem. Int. Ed. 2016, 55, 2911-2915
- Chemoproteomics‐Enabled De Novo Discovery of Photoswitchable Carboxylesterase Inhibitors for Optically Controlled Drug Metabolism
Brendan Dwyer,# Chao Wang,# Daniel Abegg, Brittney Racioppo, Nan Qiu, Zhensheng Zhao, Dany Pechalrieu, Anton Shuster, Dominic Hoch, Alexander Adibekian*
Angew. Chem. Int. Ed. 2021, 60, 3071-3079
D. Small MW tags for transporter-mediated cellular delivery
We are designing and synthesizing small MW covalent-reversible tags which bind to specific cell surface proteins and enable cellular delivery of otherwise impermeable cargos such as peptides, proteins and nucleic acids.
- Strained Cyclic Disulfides Enable Cellular Uptake by Reacting with the Transferrin Receptor
Daniel Abegg, Giulio Gasparini, Dominic G. Hoch, Anton Shuster, Eline Bartolami, Stefan Matile*, Alexander Adibekian*
J. Am. Chem. Soc. 2017, 139, 231-238
For more information, please visit our group webpage or directly contact Dr. Adibekian (firstname.lastname@example.org).
Postdoc – The Scripps Research Institute, La Jolla, CA (Advisor: Dr. Ben Cravatt)
PhD – ETH Zurich, Switzerland (Advisor: Dr. Peter Seeberger)
BSc, MSc – Leibniz University Hannover, Germany (Advisor: Dr. Andreas Kirschning)