Search results for "Protease"
showing 10 items of 463 documents
LC–MS Based Cleavage Site Profiling of the Proteases ADAM10 and ADAM17 Using Proteome-Derived Peptide Libraries
2014
A Disintegrin and Metalloproteinase 10 (ADAM10) and ADAM17 catalyze ectodomain shedding of a number of cell surface proteins important for embryonic development and tissue homeostasis. Changes in the expression levels or dysregulated proteolytic activity of ADAM10 and ADAM17 have been shown to play important roles in multiple diseases such as inflammation, cancer, and neurodegenerative disorders. Despite the well documented substrate repertoire of ADAM10 and ADAM17, little is known about their cleavage site specificity. We optimized Q-PICS (Quantitative Proteomics for the Identification of Cleavage Sites) to elucidate the cleavage site specificity of recombinant murine ADAM10 and ADAM17. Tw…
Proteomics of Galápagos Marine Iguanas Links Function of Femoral Gland Proteins to the Immune System
2020
Femoral glands secrete a wax-like substance on the inner side of lizard hind legs, which is thought to function as a mode of chemical communication. Though the minor volatile fraction is well studied, the major protein fraction remains enigmatic. Here, we use proteomics to analyze proteins in femoral gland secretions of the Galápagos marine iguana. Although we found no evidence for proteins and peptides involved in chemical communication, we found several immune-regulatory proteins which also demonstrate anti-microbial functions. Accordingly, we show that femoral gland proteins and peptides function as a barrier against microbial infection and may prevent the rapid degradation of volatile s…
The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10
2012
The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin…
Future Directions in the Pharmacologic Therapy of Chronic Obstructive Pulmonary Disease
2005
Current therapy for chronic obstructive pulmonary disease (COPD) fails to alter its relentless progression. This remains a significant challenge and unmet need. A recent advance is the demonstration that treatment with a fixed dose of an inhaled corticosteroid and a long-acting beta2-agonist in COPD improves lung function and quality of life, and reduces exacerbation more effectively than either drug alone. Other improvements include the introduction of tiotropium, a once-daily anticholinergic. In advanced clinical development are other once-daily bronchodilators and combinations of anticholinergic drugs and beta2-agonists. Increased understanding of the pathogenesis of COPD has led to nove…
Cardioprotective effects of the serine protease inhibitor aprotinin after regional ischemia and reperfusion on the beating heart.
2002
AbstractObjective: Early coronary reperfusion of the ischemic myocardium is a desired therapeutic goal to preserve myocardium. However, reperfusion itself contributes to an additional myocardial injury (ie, reperfusion injury), which has been attributed to neutrophil infiltration with subsequent release of proteases and oxygen-derived radicals. We studied the effects of the serine protease inhibitor aprotinin (Trasylol) on myocardial ischemia and reperfusion in a rat model. Methods: The effects of aprotinin (5000 and 20,000 U/kg) were examined in vivo in a rat model of regional myocardial ischemia (20 minutes) and long-term reperfusion (24 hours). Cardioprotecive effects were determined by …
Binding and Reactivity of a Nitrile Oral Inhibitor of SARS-CoV-2 Main Protease Revealed by Computational Simulations
2021
We present a detailed analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against SARS-CoV-2 3CL protease. Classical and QM/MM Molecular Dynamics simulations are used to quantify the contributions to the binding free energy and the reaction mechanism for covalent inhibition. The small size of the nitrile warhead conferes additional advantadges to this inhibitor.
In silico molecular investigations of pyridine N-Oxide compounds as potential inhibitors of SARS-CoV-2: 3D QSAR, molecular docking modeling, and ADME…
2020
The new coronavirus SARS-CoV-2 virus is causing a severe pneumonia in human, provoking the serious outbreak epidemic CoV-2. Since its appearance in Wuhan, China on December 2019, CoV-2 becomes the biggest challenge the world is facing today, including the discovery of antiviral drug for SARS-CoV-2. In this study, the potential inhibitory of a class of human SARS inhibitors, namely pyridine N-oxide derivatives, against CoV-2 was addressed by quantitative structure-activity relationship 3 D-QSAR. The reliable CoMSIA developed model of 110 pyridine N-oxide based-antiviral compounds, showed Q
Molecular modelling and QSAR in the discovery of HIV-1 integrase inhibitors
2007
The treatment regimens for the HIV-1 have mainly included reverse transcriptase or protease inhibitors but their long-term clinical utility is limited by severe side effects and viral drug resistance. A new attractive target for chemotherapeutic intervention can be the Integrase enzyme, that mediates the integration of HIV-1 DNA into a host chromosome, for which there is no known counterparts in the host cell. A number of derivatives have been found to inhibit IN in in vitro assays, but no successful drug based on them has emerged so far, although many compounds have been proposed. Moreover most of the inhibitors do not belong to a very precise structural class: this fact makes these compou…
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.