A5048271807- SARS-CoV-2 and COVID-19 Research
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- interferon and immune responses
- Protein Structure and Dynamics
- Synthesis and biological activity
- RNA Interference and Gene Delivery
- Peptidase Inhibition and Analysis
- COVID-19 Clinical Research Studies
- Diverse Scientific Research Studies
- Biocrusts and Microbial Ecology
- Advanced X-ray Imaging Techniques
- RNA and protein synthesis mechanisms
- Viral Infections and Immunology Research
- Phagocytosis and Immune Regulation
- Antimicrobial Peptides and Activities
- Crystallization and Solubility Studies
- Infectious Encephalopathies and Encephalitis
- Machine Learning in Bioinformatics
- Calpain Protease Function and Regulation
- Synthesis and Characterization of Heterocyclic Compounds
- Enzyme Production and Characterization
- Cell death mechanisms and regulation
- X-ray Diffraction in Crystallography
- thermodynamics and calorimetric analyses
Deutsches Elektronen-Synchrotron DESY
2017-2024
Center for Free-Electron Laser Science
2019-2024
Universität Hamburg
2019-2024
Technical University of Munich
2021
Coherent (Germany)
2021
Leibniz University Hannover
2021
Helmholtz-Zentrum Berlin für Materialien und Energie
2021
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug available to directly treat the disease. In a search for against COVID-19, we have performed high-throughput x-ray crystallographic screen of two repurposing libraries main protease (M
Serial X-ray crystallography allows macromolecular structure determination at both free electron lasers (XFELs) and, more recently, synchrotron sources. The time resolution for serial experiments has been limited to millisecond timescales with monochromatic beams. polychromatic, "pink", beam provides a than two orders of magnitude increased photon flux and hence accessing much shorter in diffraction Here we report the different protein samples by merging pink-beam patterns from many...
Unravelling the interaction of biological macromolecules with ligands and substrates at high spatial temporal resolution remains a major challenge in structural biology. The development serial crystallography methods X-ray free-electron lasers subsequently synchrotron light sources allows new approaches to tackle this challenge. Here, polyimide tape drive designed for mix-and-diffuse experiments is reported. structure lysozyme bound by competitive inhibitor chitotriose was determined using...
SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of viral polypeptide chain, PLpro has additional and vital function removing ubiquitin ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading host's innate immune responses. We identified three phenolic compounds bound PLpro, preventing essential molecular interactions by screening a natural compound library. The X-ray...
Efficient and reliable sample delivery has remained one of the bottlenecks for serial crystallography experiments. Compared with other methods, fixed-target offers advantage significantly reduced consumption shorter data collection times owing to higher hit rates. Here, a new method on-chip crystallization is reported which allows efficient reproducible growth large numbers protein crystals directly on micro-patterned silicon chips in-situ Crystals are grown by sitting-drop vapor diffusion...
Emerging RNA viruses, including SARS-CoV-2, continue to be a major threat. Cell entry of SARS-CoV-2 particles via the endosomal pathway involves cysteine cathepsins. Due ubiquitous expression, cathepsin L (CatL) is considered promising drug target in context different viral and lysosome-related diseases. We characterized anti-SARS-CoV-2 activity set carbonyl- succinyl epoxide-based inhibitors, which were previously identified as inhibitors cathepsins or related proteases. Calpain inhibitor...
Reliable sample delivery and efficient use of limited beam time have remained bottlenecks for serial crystallography (SX). Using a high-intensity polychromatic X-ray in combination with newly developed charge-integrating JUNGFRAU detector, we applied the method fixed-target SX to collect data at rate 1 kHz synchrotron-radiation facility. According our analysis given experimental conditions, only about 3 000 diffraction patterns are required high-quality dataset. With indexing rates up 25%,...
Several drug screening campaigns identified Calpeptin as a candidate against SARS-CoV-2. Initially reported to target the viral main protease (Mpro), its moderate activity in Mpro inhibition assays hints at second target. Indeed, we show that is an extremely potent cysteine cathepsin inhibitor, finding additionally supported by X-ray crystallography. Cell infection proved Calpeptin's efficacy Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated dose 1 mg/kg body weight...
The main protease (Mpro) of SARS-CoV-2 is critical for viral function and a key drug target. Mpro only active when reduced; turnover ceases upon oxidation but restored by re-reduction. This suggests the system has evolved to survive periods in an oxidative environment, mechanism this protection not been confirmed. Here, we report crystal structure oxidized showing disulfide bond between site cysteine, C145, distal C117. Previous work proposed provides from irreversible oxidation. forms...
The papain-like protease (PLpro) of SARS-CoV-2 is essential for viral propagation and, additionally, dysregulation the host innate immune system. Using a library 40 potential metal-chelating compounds we performed an X-ray crystallographic screening against PLpro. As outcome identified six binding to target protein. Here describe interaction one hydrazone (H1) and five thiosemicarbazone (T1-T5) with two distinct natural substrate sites PLpro ubiquitin ISG15. H1 binds polar groove at S1 site...
Abstract The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug available to directly treat the prevent virus spreading. In a search against COVID-19, we have performed massive X-ray crystallographic screen of two repurposing libraries main protease (M pro ), which essential replication and, thus, potent target. contrast commonly applied fragment screening experiments with molecules low...
Abstract Here we present the crystal structure of SARS-CoV-2 main protease (M pro ) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization M with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in framework a large X-ray crystallographic screening project against drug repurposing library, consisting 5632 approved drugs or compounds clinical phase trials. Further investigations showed that is cleaved an E1cB-like reaction...
Abstract Protein adaptations to extreme environmental conditions are drivers in biotechnological process optimization and essential unravel the molecular limits of life. Most proteins with such desirable found extremophilic organisms inhabiting environments. The deep sea is an environment a promising resource that poses multiple extremes on its inhabitants. Conditions like high hydrostatic pressure or low temperature prevalent many deep‐sea tolerate these extremes. While comparatively good...
Abstract Several drug screening campaigns identified Calpeptin as a candidate against SARS-CoV-2. Initially reported to target the viral main protease (Mpro), its moderate activity in Mpro inhibition assays hints at second target. Indeed, we show that is an extremely potent cysteine cathepsin inhibitor, finding additionally supported by X-ray crystallography. Cell infection proved Calpeptin’s efficacy Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated dose 1 mg/kg body...
Abstract SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, PLpro has additional and vital function of removing ubiquitin ISG15 (Interferon-stimulated gene 15) from host-cell proteins to aid coronaviruses in evading host’s innate immune responses. We established a high-throughput X-ray screening identify inhibitors by elucidating native structure refined 1.42 Å performing co-crystallization utilizing diverse library selected natural...
Abstract Emerging RNA viruses including SARS-CoV-2 continue to be a major threat around the globe. The cell entry of particles via endosomal pathway involves cysteine protease cathepsin L (CatL) among other proteases. CatL is rendered as promising drug target in context different viral and lysosome-related diseases. Hence, discovery structure-based optimization inhibitors high pharmaceutical interest. We herein verified compared anti-SARS-CoV-2 activity set carbonyl succinyl-epoxide-based...