A5006545278- Protease and Inhibitor Mechanisms
- Blood Coagulation and Thrombosis Mechanisms
- Signaling Pathways in Disease
- Antiplatelet Therapy and Cardiovascular Diseases
- Phytochemistry and Bioactive Compounds
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Platelet Disorders and Treatments
- Receptor Mechanisms and Signaling
- Peptidase Inhibition and Analysis
- Cell Adhesion Molecules Research
- Neuropeptides and Animal Physiology
- Connective Tissue Growth Factor Research
- Chemokine receptors and signaling
- Angiogenesis and VEGF in Cancer
- Biomarkers in Disease Mechanisms
- Cancer Mechanisms and Therapy
- Enzyme Structure and Function
- Diet, Metabolism, and Disease
- Vitamin K Research Studies
- Venous Thromboembolism Diagnosis and Management
- Acute Myocardial Infarction Research
- Liver Disease Diagnosis and Treatment
- Atrial Fibrillation Management and Outcomes
- Biochemical and Structural Characterization
- Protein Structure and Dynamics
Tufts Medical Center
2013-2023
Molecular Oncology (United States)
2008-2023
Tufts University
2014-2023
Sinai Hospital
2015-2021
Lahey Hospital and Medical Center
2013
Mount Auburn Hospital
2011-2013
Oregon Health & Science University
2012
Arthur M. Sackler Gallery
2012
In-Q-Tel
2011
Immunovaccine (Canada)
2009
Classical ligands bind to the extracellular surface of their cognate receptors and activate signaling pathways without crossing plasma membrane barrier. We selectively targeted intracellular receptor–G protein interface by using cell-penetrating membrane-tethered peptides. Attachment a palmitate group peptides derived from third loop protease-activated receptors-1 -2 melanocortin-4 yields agonists and/or antagonists signaling. These lipidated peptides—which we have termed pepducins—require...
Thrombin activates platelets in an ordered sequence of events that includes shape change, increase cytoplasmic Ca2+, activation the αIIbβ3 integrin, granule secretion, aggregation, and formation a stable hemostatic plug. Activation this process has also been implicated pathogenesis atherosclerosis, stroke, thrombosis. There are two identified thrombin-activated receptors on surface human platelets. PAR1 is high-affinity thrombin receptor, PAR4 low apparent affinity receptor uncertain...
Conventional calpains are ubiquitous calcium-regulated cysteine proteases that have been implicated in cytoskeletal organization, cell proliferation, apoptosis, motility, and hemostasis. There two forms of conventional calpains: the μ-calpain, or calpain I, which requires micromolar calcium for half-maximal activation, m-calpain, II, functions at millimolar concentrations. We evaluated functional role 80-kDa catalytic subunit μ-calpain by genetic inactivation using homologous recombination...
It has been hypothesized that protease-activated receptors may be activated and attenuated by more than one protease. Here, we explore a desensitization mechanism of the PAR1 thrombin receptor anticoagulant proteases provide an explanation to enigma why plasmin/tissue plasminogen activator (t-PA) can both activate deactivate platelets prior treatment. By using soluble N-terminal exodomain (TR78) as model for full-length receptor, were able unambiguously compare cleavage rates specificities...
Thrombin is the most potent agonist of platelets and plays a critical role in development arterial thrombosis. Human express dual thrombin receptors, protease-activated receptor (PAR) 1 PAR4; however, there are no therapeutic strategies that effectively target both receptors.Platelet aggregation studies demonstrated PAR4 activity markedly enhanced by thrombin-PAR1 interactions. A combination bivalirudin (hirulog) plus novel pepducin antagonist, P4pal-i1, inhibited human to even high...
Abstract Protease-activated receptor 1 (PAR1) is a G protein–coupled that not expressed in normal breast epithelia but up-regulated invasive carcinomas. In the present study, we found matrix metalloprotease-1 (MMP-1) robustly activates PAR1-Akt survival pathway carcinoma cells. This process blocked by cell-penetrating lipopeptide “pepducin,” P1pal-7, which potent inhibitor of cell viability cells expressing PAR1. Both MMP-1 and P1pal-7 significantly promote apoptosis tumor xenografts inhibit...
Pepducins are membrane-tethered, cell-penetrating lipopeptides that target the cytoplasmic surface of their cognate receptor. Here, we report first human use a protease-activated receptor-1-based pepducin, which is intended as an antiplatelet agent to prevent ischemic complications percutaneous coronary interventions.PZ-128 was administered by 1 2 hours continuous intravenous infusion (0.01-2 mg/kg) 31 subjects with artery disease or multiple risk factors. Safety, efficacy, and...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTProduction, Purification, and Cleavage of Tandem Repeats Recombinant PeptidesAthan Kuliopulos Christopher T. WalshCite this: J. Am. Chem. Soc. 1994, 116, 11, 4599–4607Publication Date (Print):June 1, 1994Publication History Published online1 May 2002Published inissue 1 June 1994https://pubs.acs.org/doi/10.1021/ja00090a008https://doi.org/10.1021/ja00090a008research-articleACS PublicationsRequest reuse permissionsArticle...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTKinetic and ultraviolet spectroscopic studies of active-site mutants .DELTA.5-3-ketosteroid isomeraseAthan Kuliopulos, Albert S. Mildvan, David Shortle, Paul TalalayCite this: Biochemistry 1989, 28, 1, 149–159Publication Date (Print):January 10, 1989Publication History Published online1 May 2002Published inissue 10 January 1989https://pubs.acs.org/doi/10.1021/bi00427a022https://doi.org/10.1021/bi00427a022research-articleACS PublicationsRequest...
Protease-activated receptor-2 (PAR2), a cell surface receptor for trypsin-like proteases, plays key role in number of acute and chronic inflammatory diseases the joints, lungs, brain, gastrointestinal tract, vascular systems. Despite considerable effort by pharmaceutical industry, PAR2 has proven recalcitrant to targeting small molecule inhibitors, which have been unable effectively prevent interaction protease-generated tethered ligand with body receptor. Here, we report development...
Abstract Sepsis is a deadly disease characterized by the inability to regulate inflammatory–coagulation response in which endothelium plays key role. The cause of this perturbation remains poorly understood and has hampered development effective therapeutics. Matrix metalloproteases (MMPs) are involved host pathogens, but can also uncontrolled tissue damage contribute mortality. We found that human sepsis patients had markedly elevated plasma proMMP‐1 active MMP‐1 levels, correlated with...
Abstract Ovarian cancer is a lethal gynecologic malignancy that may benefit from new therapies block key paracrine pathways involved in tumor-stromal interactions and tumor vascularity. It was recently shown matrix metalloprotease-1 (MMP1) activation of the G protein–coupled receptor protease-activated receptor-1 (PAR1) an important stimulator angiogenesis metastasis peritoneal mouse models ovarian cancer. In present study, we tested hypothesis MMP1-PAR1 promotes through its control...
Gene chip and proteomic analyses of tumors stromal tissue has led to the identification dozens candidate tumor host components potentially involved in tumor-stromal interactions, angiogenesis, progression invasive disease. In particular, matrix metalloproteases (MMP) have emerged as important biomarkers prognostic factors for metastatic cancers. From an initial screen benign versus malignant patient fluids, we delineated a metalloprotease cascade comprising MMP-14, MMP-9, MMP-1 that...