Search results for "PROTEASES"
showing 10 items of 196 documents
Anti-prothrombin autoantibodies enriched after infection with SARS-CoV-2 and influenced by strength of antibody response against SARS-CoV-2 proteins
2021
Antiphospholipid antibodies (aPL), assumed to cause antiphospholipid syndrome (APS), are notorious for their heterogeneity in targeting phospholipids and phospholipid-binding proteins. The persistent presence of Lupus anticoagulant and/or aPL against cardiolipin and/or β2-glycoprotein I have been shown to be independent risk factors for vascular thrombosis and pregnancy morbidity in APS. aPL production is thought to be triggered by–among other factors–viral infections, though infection-associated aPL have mostly been considered non-pathogenic. Recently, the potential pathogenicity of infection-associated aPL has gained momentum since an increasing number of patients infected with Severe Acu…
Computational simulations on the binding and reactivity of a nitrile inhibitor of the SARS-CoV-2 main protease.
2021
We present a detailed computational analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against the SARS-CoV-2 3CL protease. Alchemical free energy calculations suggest that positions P3 and P4 could be susceptible to improvement in order to get a larger binding strength. QM/MM simulations unveil the reaction mechanism for covalent inhibition, showing that the nitrile warhead facilitates the recruitment of a water molecule for the proton transfer step.
Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure-Activity Relationship Insights and Evolution Perspectives
2022
The viral main protease is one of the most attractive targets among all key enzymes involved in the SARS-CoV-2 life cycle. Covalent inhibition of the cysteine145 of SARS-CoV-2 MPRO with selective antiviral drugs will arrest the replication process of the virus without affecting human catalytic pathways. In this Perspective, we analyzed the in silico, in vitro, and in vivo data of the most representative examples of covalent SARS-CoV-2 MPRO inhibitors reported in the literature to date. In particular, the studied molecules were classified into eight different categories according to their reactive electrophilic warheads, highlighting the differences between their reversible/irreversible mech…
Heteroaromatic Inhibitors of the Astacin Proteinases Meprin α, Meprin β and Ovastacin Discovered by a Scaffold-Hopping Approach.
2020
Abstract Astacin metalloproteinases, in particular meprins α and β, as well as ovastacin, are emerging drug targets. Drug‐discovery efforts have led to the development of the first potent and selective inhibitors in the last few years. However, the most recent compounds are based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or decreased potency due to the entropic penalty upon binding to the target. Thus, the aim of this study was to discover novel conformationally constrained scaffolds as starting points for further inhibitor optimization. Shifting from flexible tertiary amines to rigid heteroaromatic cores resulted in a boost in inhibitory activity. …
Type-II Transmembrane Prolyl Dipeptidases and Matrix Metalloproteinases in Membrane Vesicles of Active Endothelial Cells
2006
Endothelia cells in sparse culture are migratory and increase the production of gelatinases of serine- and metallo-classes in membrane vesicles. Collectively, proteases associated with membrane vesicles degrade extracellular matrix components including type-I and type-IV collagens, laminin and fibronectin. Inhibitor studies suggest the existence of small gelatinases that were derived from these serine- and metallo-proteases. Thus, further studies are warranted to demonstrate the cooperative action of metallo- and serine proteases on cell surfaces and in extracellular vesicles during endothelial cell migration in 3D collagenous matrices, and potential proteolytic activation mechanism for the…
Melanoma cells release extracellular vesicles which contain RNA-binding proteins able to bind the mRNA encoding histone H1°
2015
Extracellular vesicles (EVs) are produced by most prokaryotic and eukaryotic cells; tumour cells, however, release much higher amounts of EVs, which contain cancer-specific proteins and RNAs. Molecules carried by EVs are captured by surrounding cells, which then undergo profound phenotypic modifications. G26/24 oligodendroglioma cells release, for example, EVs containing FasL and TRAIL, which induce apoptosis in rat cortical neurons and astrocytes in culture. By metabolic labelling of cells, EV-mediated horizontal transfer of radioactive proteins was clearly demonstrated. Among the proteins present in EVs produced by oligodendroglioma cells, extracellular matrix remodelling proteases, and t…
RNA as a carrier of epigenetic information
2017
Both prokaryotic and eukaryotic cells release into the extracellular matrix membrane-bound structures of different sizes, origin and composition, collectively called extracellular vesicles (EVs) [1]. Tumor cells, in particular, use EVs to transfer both nucleic acids and proteins to the surrounding normal cells, thus inducing in them transformed behaviours or killing them. G26/24 oligodendroglioma cells, for example, transfer by EVs pro-apoptotic proteins, such as TRAIL and Fas-Ligand [2], extracellular matrix remodelling proteases (such as ADAMTS) [3], and even the H1.0 histone protein [4]. Another tumour cell line, with a different tissue origin (A375 melanoma cells) releases into the medi…
Novel pathogenic mechanism of microbial metalloproteinases: liberation of membrane-anchored molecules in biologically active form exemplified by stud…
1996
Certain membrane-anchored proteins, including several cytokines and cytokine receptors, can be released into cell supernatants through the action of endogenous membrane-bound metalloproteinases. The shed molecules are then able to fulfill various biological functions; for example, soluble interleukin-6 receptor (sIL-6R) can bind to bystander cells, rendering these cells sensitive to the action of IL-6. Using IL-6R as a model substrate, we report that the metalloproteinase from Serratia marcescens mimics the action of the endogenous shedding proteinase. Treatment of human monocytes with the bacterial protease led to a rapid release of sIL-6R into the supernatant. This effect was inhibitable …
Inactivation of the ftsH gene of Lactobacillus plantarum WCFS1: Effects on growth, stress tolerance, cell surface properties and biofilm formation
2012
FtsH proteins are ubiquitous membrane-bound, ATP-dependent metalloproteases of the AAA family. In eubacteria, FtsH is involved in protein quality control under stress conditions. Lactobacillus plantarum is a widespread lactic acid bacterium that is encountered in several fermented food, including dairy products, vegetables and meat. In the present work the expression of the ftsH gene of L. plantarum was studied by quantitative real time RT-PCR in bacterial cultures subjected to various abiotic stresses. Both oxidative stress and addition of a membrane-fluidizing agent induced ftsH transcription, while a depletion of carbon-source repressed its mRNA level. Mutants deprived of the FtsH protea…
The Swedish dilemma - the almost exclusive use of APPswe-based mouse models impedes adequate evaluation of alternative β-secretases.
2022
Abstract Alzheimer's disease (AD) is the most common form of dementia, however incurable so far. It is widely accepted that aggregated amyloid β (Aβ) peptides play a crucial role for the pathogenesis of AD, as they cause neurotoxicity and deposit as so-called Aβ plaques in AD patient brains. Aβ peptides derive from the amyloid precursor protein (APP) upon consecutive cleavage at the β- and γ-secretase site. Hence, mutations in the APP gene are often associated with autosomal dominant inherited AD. Almost thirty years ago, two mutations at the β-secretase site were observed in two Swedish families (termed Swedish APP (APPswe) mutations), which led to early-onset AD. Consequently, APPswe was …