A5000997540- Peptidase Inhibition and Analysis
- Ubiquitin and proteasome pathways
- Protease and Inhibitor Mechanisms
- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- Cell death mechanisms and regulation
- Advanced biosensing and bioanalysis techniques
- SARS-CoV-2 and COVID-19 Research
- Neuropeptides and Animal Physiology
- Organophosphorus compounds synthesis
- RNA Interference and Gene Delivery
- Malaria Research and Control
- Computational Drug Discovery Methods
- Enzyme Production and Characterization
- Natural product bioactivities and synthesis
- Biochemical and Structural Characterization
- Glycosylation and Glycoproteins Research
- interferon and immune responses
- Pneumocystis jirovecii pneumonia detection and treatment
- Antimicrobial Peptides and Activities
- Microbial Metabolism and Applications
- Studies on Chitinases and Chitosanases
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Synthesis and Reactivity of Sulfur-Containing Compounds
- NF-κB Signaling Pathways
Wrocław University of Science and Technology
2016-2025
AGH University of Krakow
2017-2025
Brunel University of London
2024
International Institute of Molecular and Cell Biology
2024
University of Gdańsk
2024
KTH Royal Institute of Technology
2024
Instytut Biologii Doświadczalnej im. Marcelego Nenckiego
2024
Sanford Burnham Prebys Medical Discovery Institute
2007-2020
Discovery Institute
2019-2020
Faculty (United Kingdom)
2016-2019
Viral papain-like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target the development of antiviral drugs. Here, we used combinatorial substrate library performed comprehensive activity profiling PLpro. On scaffold best hits from positional scanning, designed optimal fluorogenic substrates irreversible inhibitors with high degree selectivity SARS We determined crystal structures two these in complex PLpro that reveals their inhibitory...
In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed. Currently, there is no effective antiviral treatment for COVID-19. To address this emerging problem, we focused on SARS-CoV-2 main protease that constitutes one most attractive drug targets. We have synthesized combinatorial library fluorogenic substrates glutamine in P1 position. used it to determine substrate preferences SARS-CoV and proteases. On basis these findings, designed potent...
The NLRP3 inflammasome responds to infection and tissue damage, rapidly escalates the intensity of inflammation by activating interleukin (IL)-1β, IL-18 cell death pyroptosis. How is negatively regulated poorly understood. Here we show that activation suppressed sumoylation. sumoylated SUMO E3-ligase MAPL, stimulation-dependent desumoylation SUMO-specific proteases SENP6 SENP7 promotes activation. Defective sumoylation, either mutation acceptor lysines or depletion results in enhanced...
The main protease of SARS-CoV-2 (Mpro) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there a concern that mutations Mpro may alter structural and functional properties subsequently potency existing potential antivirals. We explored effect 31 belonging 5 (VOCs) on catalytic parameters substrate specificity, which revealed changes binding rate cleavage viral peptide. Crystal structures 11 mutants provided...
Caspase 8 is an initiator caspase that activated by death receptors to initiate the extrinsic pathway of apoptosis. activation involves dimerization and subsequent interdomain autoprocessing zymogens, recently published work has established elimination site abrogates its pro-apoptotic function while leaving proliferative intact. The observation developmental abnormalities 8-deficient mice are shared lacking adapter FADD (Fas-associated domain) or paralogue FLIPL [FLICE (FADD-like interleukin...
Significance The exploration of protease substrate specificity is generally restricted to naturally occurring amino acids, limiting the degree conformational space that can be surveyed. We substantially enhanced this by incorporating 102 unnatural acids explore S1–S4 pockets human neutrophil elastase. This approach provides hybrid natural and acid sequences, thus we termed it Hybrid Combinatorial Substrate Library. Using approach, have designed an extremely active NE subsequently converted...
SENPs are proteases that participate in the regulation of SUMOylation by generating mature small ubiquitin-related modifiers (SUMO) for protein conjugation (endopeptidase activity) and removing conjugated SUMO from targets (isopeptidase activity). Using purified recombinant catalytic domains 6 7 human SENPs, we demonstrate specificity their respective activities on SUMO-1, -2, -3. The primary mode recognition substrates is via domain, C-terminal tails direct endopeptidase specificity....
The caspase-3 zymogen has essentially zero activity until it is cleaved by initiator caspases during apoptosis. However, a mutation of V266E in the dimer interface activates protease absence chain cleavage. We show that low concentrations pseudo-activated procaspase-3 kill mammalian cells rapidly and, importantly, this protein not nor inhibited efficiently endogenous regulator XIAP (X-linked inhibitor apoptosis). 1.63 Å (1 = 0.1 nm) structure variant demonstrates accommodated at to generate...
Neutrophils, the front line defenders against infection, express four serine proteases (NSPs) that play roles in control of cell-signaling pathways and defense pathogens whose imbalance leads to pathological conditions. Dissecting individual NSPs humans is problematic because neutrophils are end-stage cells with a short half-life minimal ongoing protein synthesis. To gain insight into regulation NSP activity we have generated small-molecule chemical toolbox consisting activity-based probes...
Inflammatory cell death, or pyroptosis, is triggered by pathogenic infections events. It executed caspase-1 (in the canonical pyroptosis pathway) caspase-11 (noncanonical pathway), each via production of a cell-lytic domain from effector protein gasdermin D through specific and limited proteolysis. Pyroptosis accompanied release inflammatory mediators, including proteolytically processed forms interleukin-1β (IL-1β) IL-18. Given similar outcomes noncanonical pathways, we hypothesized that...
Abstract In December 2019, the first cases of a novel coronavirus infection causing COVID-19 were diagnosed in Wuhan, China. Viral Papain-Like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents promising target development antiviral drugs. Here, we used combinatorial substrate library containing natural wide variety nonproteinogenic amino acids performed comprehensive activity profiling SARS-CoV-2-PLpro. On scaffold best hits from positional scanning...
The main viral protease (3CL
Abstract Proteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. main protease (M pro , 3CL ) and papain-like (PL are responsible viral polyprotein cleavage—a process crucial survival replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2 H )-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is potent, covalent inhibitor of both the proteases its potency evaluated in enzymatic antiviral assays. In this study, we...
The covalent attachment of SUMO (small ubiquitin-like protein modifier) to target proteins results in modifications their activity, binding interactions, localization or half-life. reversal this modification is catalysed by SENPs (SUMO-specific processing proteases). Mammals contain four paralogues and six SENP enzymes. In the present paper, we describe a systematic analysis human SENPs, integrating estimates relative selectivity for SUMO1 SUMO2, kinetic measurements recombinant C-terminal...
ERAP1 (endoplasmic reticulum aminopeptidase 1), ERAP2 and IRAP (insulin-regulated aminopeptidase) are three homologous enzymes that play critical roles in the generation of antigenic peptides. These aminopeptidases excise amino acids from N-terminally extended precursors peptides order to generate correct length epitopes for binding on MHC class I molecules. The specificity these peptidases can affect peptide selection, but has not yet been investigated detail. In present study we utilized a...