21,373 results match your criteria inhibitors proteolytic


Mechanism of inhibition of SARS-CoV-2 M by peptidyl Michael acceptor explained by QM/MM simulations and design of new derivatives with tunable chemical reactivity.

Chem Sci 2020 Nov 27;12(4):1433-1444. Epub 2020 Nov 27.

Departament de Química Física i Analítica, Universitat Jaume I 12071 Castelló Spain

The SARS-CoV-2 main protease (M) is essential for replication of the virus responsible for the COVID-19 pandemic, and one of the main targets for drug design. Here, we simulate the inhibition process of SARS-CoV-2 M with a known Michael acceptor (peptidyl) inhibitor, . The free energy landscape for the mechanism of the formation of the covalent enzyme-inhibitor product is computed with QM/MM molecular dynamics methods. Read More

View Article and Full-Text PDF
November 2020

TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells.

EMBO J 2021 Jun 23:e107821. Epub 2021 Jun 23.

Center for Integrative Infectious Diseases Research (CIID), University Hospital Heidelberg, 69120, Heidelberg, Germany.

SARS-CoV-2 is a newly emerged coronavirus that caused the global COVID-19 outbreak in early 2020. COVID-19 is primarily associated with lung injury, but many other clinical symptoms such as loss of smell and taste demonstrated broad tissue tropism of the virus. Early SARS-CoV-2-host cell interactions and entry mechanisms remain poorly understood. Read More

View Article and Full-Text PDF

Differential Neuropeptidomes of Dense Core Secretory Vesicles (DCSV) Produced at Intravesicular and Extracellular pH Conditions by Proteolytic Processing.

ACS Chem Neurosci 2021 Jun 21. Epub 2021 Jun 21.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States.

Neuropeptides mediate cell-cell signaling in the nervous and endocrine systems. The neuropeptidome is the spectrum of peptides generated from precursors by proteolysis within dense core secretory vesicles (DCSV). DCSV neuropeptides and contents are released to the extracellular environment where further processing for neuropeptide formation may occur. Read More

View Article and Full-Text PDF

An Integrated Molecular Grafting Approach for the Design of Keap1-Targeted Peptide Inhibitors.

ACS Chem Biol 2021 Jun 21. Epub 2021 Jun 21.

Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia.

Inhibiting the Nrf2:Keap1 interaction to trigger cytoprotective gene expression is a promising treatment strategy for oxidative stress-related diseases. A short linear motif from Nrf2 has the potential to directly inhibit this protein-protein interaction, but poor stability and limited cellular uptake impede its therapeutic development. To address these limitations, we utilized an integrated molecular grafting strategy to re-engineer the Nrf2 motif. Read More

View Article and Full-Text PDF

PROTACs, molecular glues and bifunctionals from bench to bedside: Unlocking the clinical potential of catalytic drugs.

Prog Med Chem 2021 27;60:67-190. Epub 2021 Mar 27.

Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, United Kingdom. Electronic address:

The vast majority of currently marketed drugs rely on small molecules with an 'occupancy-driven' mechanism of action (MOA). Therefore, the efficacy of these therapeutics depends on a high degree of target engagement, which often requires high dosages and enhanced drug exposure at the target site, thus increasing the risk of off-target toxicities (Churcher, 2018 [1]). Although small molecule drugs have been successfully used as treatments for decades, tackling a variety of disease-relevant targets with a defined binding site, many relevant therapeutic targets remain challenging to drug due, for example, to lack of well-defined binding pockets or large protein-protein interaction (PPI) interfaces which resist interference (Dang et al. Read More

View Article and Full-Text PDF

[Development of antiviral drugs based on inhibitors of the SARS-COV-2 main protease].

Biomed Khim 2021 May;67(3):259-267

Research Computer Center of Lomonosov Moscow State University, Moscow, Russia; Dimonta Ltd., Moscow, Russia.

Docking and quantum-chemical methods have been used for screening of drug-like compounds from the own database of the Voronezh State University to find inhibitors the SARS-CoV-2 main protease, an important enzyme of the coronavirus responsible for the COVID-19 pandemic. Using the SOL program more than 42000 3D molecular structures were docked into the active site of the main protease, and more than 1000 ligands with most negative values of the SOL score were selected for further processing. For all these top ligands, the protein-ligand binding enthalpy has been calculated using the PM7 semiempirical quantum-chemical method with the COSMO implicit solvent model. Read More

View Article and Full-Text PDF

Development of selective protease inhibitors via engineering of the bait region of human α-macroglobulin.

J Biol Chem 2021 Jun 14:100879. Epub 2021 Jun 14.

Department of Molecular Biology and Genetics, Aarhus University, Aarhus 8000, Denmark. Electronic address:

Human α-macroglobulin (A2M) is an abundant protease inhibitor in plasma which regulates many proteolytic processes and is involved in innate immunity. A2M's unique protease-trapping mechanism of inhibition is initiated when a protease cleaves within the exposed and highly susceptible "bait region". As the wildtype bait region is permissive to cleavage by most human proteases, A2M is accordingly a broad-spectrum protease inhibitor. Read More

View Article and Full-Text PDF

Suppression of cigarette smoke induced MMP1 expression by selective serotonin re-uptake inhibitors.

FASEB J 2021 Jul;35(7):e21519

Department of Medicine, Anesthesiology, Physiology and Cell Biology, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.

Globally, COPD remains a major cause of disability and death. In the United States alone, it is estimated that approximately 14 million people suffer from the disease. Given the high disease burden and requirement for chronic, long-term medical care associated with COPD, it is essential that new disease modifying agents are developed to complement the symptomatic therapeutics currently available. Read More

View Article and Full-Text PDF

A Mini Review on the Effectiveness of Peptoids as Therapeutic Interventions against Neurodegenerative Diseases.

Curr Protein Pept Sci 2021 Jun 15. Epub 2021 Jun 15.

Department of Chemistry, Cooch Behar Panchanan Barma University, Panchanan Nagar, Cooch Behar 736101, India.

Neurodegenerative diseases emerged as one of the major age-associated diseases in the recent years. Hence, the urge for understanding the mechanism and to find targeted therapeutics becomes inevitable. Peptide-based compounds emerged as one of the important tools for its therapy. Read More

View Article and Full-Text PDF

Peptidomimetics prepared by tail-to-side chain one component peptide stapling inhibit Alzheimer's amyloid-β fibrillogenesis.

Chem Sci 2020 Mar 27;11(16):4171-4179. Epub 2020 Mar 27.

Laboratory of Peptide and Amyloid Research, Department of Chemistry, Indian Institute of Technology Guwahati Assam-781039 India

Alzheimer's disease (AD) is the most common form of dementia affecting the elderly population worldwide. Despite enormous efforts and considerable advancement in research, no therapeutic agents have come to light to date. However, many peptide-based and small molecule inhibitors interact efficiently with the amyloid-β (Aβ) peptide and alter its aggregation pathway. Read More

View Article and Full-Text PDF

Development of Agonist-Based PROTACs Targeting Liver X Receptor.

Front Chem 2021 26;9:674967. Epub 2021 May 26.

Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa, Japan.

Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily and function as ligand-dependent transcription factors that regulate cholesterol homeostasis, lipid homeostasis, and immune responses. LXR antagonists are promising treatments for hypercholesterolemia and diabetes. However, effective LXR antagonists and inhibitors are yet to be developed. Read More

View Article and Full-Text PDF

Metabolic changes in synovial cells in early inflammation: Involvement of CREB phosphorylation in the anti-inflammatory effect of 2-deoxyglucose.

Arch Biochem Biophys 2021 Sep 8;708:108962. Epub 2021 Jun 8.

Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

The involvement of metabolic reprogramming has been suggested to contribute to the pathophysiology of rheumatoid arthritis (RA). Glycolysis is enhanced in synovial cell metabolism in RA patients. Inhibitors of glycolysis are known to have anti-inflammatory effects. Read More

View Article and Full-Text PDF
September 2021

Triticum monococcum amylase trypsin inhibitors possess a reduced potential to elicit innate immune response in celiac patients compared to Triticum aestivum.

Food Res Int 2021 Jul 7;145:110386. Epub 2021 May 7.

Institute of Food Sciences, CNR, Avellino, Italy; E.L.F.I.D, University "Federico II" Napoli, Italy. Electronic address:

Scope: Several studies reported a role of amylase/trypsin-inhibitors (ATIs) of common wheat species in promoting immune reactions. Here, we investigated in celiac disease (CD), the immunogenic properties of ATIs from diploid compared to common hexaploid wheats after an in vitro proteolytic hydrolysis.

Methods And Results: ATIs purified from two lines of diploid Triticum monococcum (TM), Monlis and Norberto-ID331, and from Triticum aestivum (TA), Sagittario, were digested with pepsin-chymotrypsin (PC) enzymes and analyzed using a proteomic approach, and subsequently their immune stimulatory properties were investigated on jejunal biopsies and T-cell lines from CD patients. Read More

View Article and Full-Text PDF

Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia.

Blood 2021 Jun 10. Epub 2021 Jun 10.

St Jude Children's Research Hospital, Memphis, Tennessee, United States.

CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) comprises over half of Philadelphia chromosome-like (Ph-like) ALL, is associated with poor outcome in children and adults. Overexpression of CRLF2 results in activation of JAK-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of Janus kinases show variable and limited efficacy. Here we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against Janus kinases. Read More

View Article and Full-Text PDF

Small molecule-mediated modulation of ubiquitination and neddylation improves HSC function ex vivo.

J Cell Physiol 2021 Jun 8. Epub 2021 Jun 8.

Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey.

Hematopoietic stem cells (HSCs) are particularly characterized by their quiescence and self-renewal. Cell cycle regulators tightly control quiescence and self-renewal capacity. Studies suggest that modulation of ubiquitination and neddylation could contribute to HSC function via cyclin-dependent kinase inhibitors (CDKIs). Read More

View Article and Full-Text PDF

Synergistic inhibition of two host factors that facilitate entry of Severe Acute Respiratory Syndrome Coronavirus 2.

bioRxiv 2021 Jun 1. Epub 2021 Jun 1.

Repurposing FDA-approved inhibitors able to prevent infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could provide a rapid path to establish new therapeutic options to mitigate the effects of coronavirus disease 2019 (COVID-19). Proteolytic cleavages of the spike S protein of SARS-CoV-2, mediated by the host cell proteases cathepsin and TMPRSS2, alone or in combination, are key early activation steps required for efficient infection. The PIKfyve kinase inhibitor apilimod interferes with late endosomal viral traffic, and through an ill-defined mechanism prevents infection through late endosomes mediated by cathepsin. Read More

View Article and Full-Text PDF

A Suite of Activity-Based Probes To Dissect the KLK Activome in Drug-Resistant Prostate Cancer.

J Am Chem Soc 2021 Jun 4;143(23):8911-8924. Epub 2021 Jun 4.

Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London W12 0BZ, U.K.

Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network (the KLK activome) with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors enabling simultaneous orthogonal analysis of KLK2, KLK3, and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Read More

View Article and Full-Text PDF

Fermentation of Gluten by Lactococcus lactis LLGKC18 Reduces its Antigenicity and Allergenicity.

Probiotics Antimicrob Proteins 2021 Jun 3. Epub 2021 Jun 3.

INRAE UR1268 BIA, Rue de la Géraudière, BP 71627, 44316, Nantes, France.

Wheat is a worldwide staple food, yet some people suffer from strong immunological reactions after ingesting wheat-based products. Lactic acid bacteria (LAB) constitute a promising approach to reduce wheat allergenicity because of their proteolytic system. In this study, 172 LAB strains were screened for their proteolytic activity on gluten proteins and α-amylase inhibitors (ATIs) by SDS-PAGE and RP-HPLC. Read More

View Article and Full-Text PDF

Structural insights and inhibition mechanism of TMPRSS2 by experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-coronavirus-2: A molecular modeling approach.

Inform Med Unlocked 2021 26;24:100597. Epub 2021 May 26.

Department of Microbiology, Shivaji University, Vidyanagar, Kolhapur, 416004, Maharashtra, India.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been responsible for the cause of global pandemic Covid-19 and to date, there is no effective treatment available. The spike 'S' protein of SARS-CoV-2 and ACE2 of the host cell are being targeted to design new drugs to control Covid-19. Similarly, a transmembrane serine protease, TMPRSS2 of the host cell plays a significant role in the proteolytic cleavage of viral 'S' protein helpful for the priming of ACE2 receptors and viral entry into human cells. Read More

View Article and Full-Text PDF

Local Colonic Administration of a Serine Protease Inhibitor Improves Post-Inflammatory Visceral Hypersensitivity in Rats.

Pharmaceutics 2021 May 29;13(6). Epub 2021 May 29.

Laboratory of Experimental Medicine and Pediatrics (LEMP), University of Antwerp, 2610 Wilrijk, Belgium.

Dysregulation of the protease-antiprotease balance in the gastrointestinal tract has been suggested as a mechanism underlying visceral hypersensitivity in conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). We aimed to study the potential therapeutic role of an intracolonically administered serine protease inhibitor for the treatment of abdominal pain in a post-inflammatory rat model for IBS. An enema containing 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce colitis in male Sprague-Dawley rats, whereas controls received a saline solution. Read More

View Article and Full-Text PDF

The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression.

Int J Mol Sci 2021 May 27;22(11). Epub 2021 May 27.

School of Life Sciences, Chongqing University, Chongqing 401331, China.

The cell cycle is a collection of events by which cellular components such as genetic materials and cytoplasmic components are accurately divided into two daughter cells. The cell-cycle transition is primarily driven by the activation of cyclin-dependent kinases (CDKs), the activities of which are regulated by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors (CKIs). Thus, the ubiquitin-proteasome system (UPS) plays a pivotal role in the regulation of the cell-cycle process via recognition, interaction, and ubiquitination or deubiquitination of key proteins. Read More

View Article and Full-Text PDF

Combination Treatment of OSI-906 with Aurora B Inhibitor Reduces Cell Viability via Cyclin B1 Degradation-Induced Mitotic Slippage.

Int J Mol Sci 2021 May 27;22(11). Epub 2021 May 27.

Department of Biochemistry & Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.

Insulin-like growth factor 1 receptor (IGF1R), a receptor-type tyrosine kinase, transduces signals related to cell proliferation, survival, and differentiation. We recently reported that OSI-906, an IGF1R inhibitor, in combination with the Aurora B inhibitor ZM447439 suppresses cell proliferation. However, the mechanism underlying this suppressive effect is yet to be elucidated. Read More

View Article and Full-Text PDF

Protease Inhibition-An Established Strategy to Combat Infectious Diseases.

Int J Mol Sci 2021 May 28;22(11). Epub 2021 May 28.

Biology Centre, Institute of Parasitology, Academy of Sciences of the Czech Republic, Branišovská 1160/31, CZ-37005 České Budějovice, Czech Republic.

Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite aspartyl proteases of (plasmepsins) and the Sars-CoV-2 viral proteases. Read More

View Article and Full-Text PDF

CX3CL1 Overexpression Prevents the Formation of Lung Metastases in Trastuzumab-Treated MDA-MB-453-Based Humanized Tumor Mice (HTM).

Cancers (Basel) 2021 May 18;13(10). Epub 2021 May 18.

Department of Gynecology and Obstetrics, Technical University of Munich, 81675 Munich, Germany.

CX3CL1 is a multifunctional chemokine that is involved in numerous biological processes, such as immune cell attraction and enhanced tumor immune cell interaction, but also in enhancing tumor cell proliferation and metastasis. The multifarious activity is partially determined by two CX3CL1 isoforms, a membrane-bound and a soluble version generated by proteolytic cleavage through proteases. Here, we investigated the impact of CX3CL1 overexpression in MDA-MB-453 and SK-BR-3 breast cancer cells. Read More

View Article and Full-Text PDF

Purification and Identification of Cholesterol Micelle Formation Inhibitory Peptides of Hydrolysate from High Hydrostatic Pressure-Assisted Protease Hydrolysis of Fermented Seabass Byproduct.

Int J Mol Sci 2021 May 18;22(10). Epub 2021 May 18.

Department of Food Science and Technology, Taipei University of Marine Technology, No. 212, Section 9, Yan Ping North Road, Taipei 111, Taiwan.

This research focuses on the proteolytic capacity of sea bass byproduct (SB) and their hypocholesterolemic activity via the cholesterol micelle formation (CMF) inhibition. SB was fermented with seven mixed lactic acid bacteria for 5 h at 42 °C. The lactic fermented SB was hydrolyzed with Protease N for 6 h under HHP to obtain the SB hydrolysates (HHP-assisted Protease N hydrolysis after fermentation, F-HHP-PN6). Read More

View Article and Full-Text PDF

Computational Design of Novel Allosteric Inhibitors for DegP.

Molecules 2021 May 7;26(9). Epub 2021 May 7.

Translational Bioinformatics Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India.

The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit DegP protease activity. Read More

View Article and Full-Text PDF

Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease.

Int J Mol Sci 2021 May 9;22(9). Epub 2021 May 9.

Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, UK.

Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Read More

View Article and Full-Text PDF

Tyrosine Kinase Inhibitors, Antibody-Drug Conjugates, and Proteolysis-Targeting Chimeras: The Pharmacology of Cutting-Edge Lung Cancer Therapies.

Am Soc Clin Oncol Educ Book 2021 Jun;41:e286-e293

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA.

The number of therapeutic options available for patients with advanced non-small-cell lung cancer has been led by deeper understanding of molecular drivers, immune function, and fundamental biology. In this article, we describe the relevant clinical pharmacologic characteristics of three broad classes of existing and investigational treatments, with a focus on mechanisms of action, adverse event profiles, pharmacokinetic and pharmacodynamic properties, and known and predicted resistance pathways. Specifically, within the kinase inhibitor class, agents directed against the RET, MET, and KRAS pathways are reviewed. Read More

View Article and Full-Text PDF

Combined Radiochemotherapy: Metalloproteinases Revisited.

Front Oncol 2021 13;11:676583. Epub 2021 May 13.

Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Besides cytotoxic DNA damage irradiation of tumor cells triggers multiple intra- and intercellular signaling processes, that are part of a multilayered, treatment-induced stress response at the unicellular and tumor pathophysiological level. These processes are intertwined with intrinsic and acquired resistance mechanisms to the toxic effects of ionizing radiation and thereby co-determine the tumor response to radiotherapy. Proteolysis of structural elements and bioactive signaling moieties represents a major class of posttranslational modifications regulating intra- and intercellular communication. Read More

View Article and Full-Text PDF

ADAMTS13 regulation of VWF multimer distribution in severe COVID-19.

J Thromb Haemost 2021 May 30. Epub 2021 May 30.

Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.

Background: Consistent with fulminant endothelial cell activation, elevated plasma von Willebrand factor (VWF) antigen levels have been reported in patients with COVID-19. The multimeric size and function of VWF are normally regulated through A Disintegrin And Metalloprotease with ThrombSpondin Motif type 1 motif, member 13 (ADAMTS-13)--mediated proteolysis.

Objectives: This study investigated the hypothesis that ADAMTS-13 regulation of VWF multimer distribution may be impaired in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection contributing to the observed microvascular thrombosis. Read More

View Article and Full-Text PDF