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https://www.readbyqxmd.com/read/27932157/belatacept-and-eculizumab-for-treatment-of-calcineurin-inhibitor-induced-thrombotic-microangiopathy-after-kidney-transplantation-case-report
#1
J Merola, P S Yoo, J Schaub, J D Smith, M I Rodriguez-Davalos, E Tichy, D C Mulligan, W Asch, R Formica, M Kashgarian, S Kulkarni
Thrombotic microangiopathy (TMA) after kidney transplantation is an uncommon and challenging cause of graft dysfunction and is associated with early graft loss. An idiosyncratic endothelial reaction to calcineurin inhibitors (CNIs) has been implicated as a frequent cause of TMA. This reaction is marked by uncontrolled activation of complement and subsequent cellular destruction. Usual therapy consists of withdrawal of the inciting drug and plasmapheresis to minimize levels of circulating complement. Recently, eculizumab, a monoclonal antibody to complement component C5, has been used for the treatment of atypical hemolytic uremic syndrome...
November 2016: Transplantation Proceedings
https://www.readbyqxmd.com/read/27914802/synthesis-and-in-vitro-antiproliferative-activity-of-c5-benzyl-substituted-2-amino-pyrrolo-2-3-d-pyrimidines-as-potent-hsp90-inhibitors
#2
Ju-Hyeon Lee, Sang Chul Shin, Seon Hee Seo, Young Ho Seo, Nakcheol Jeong, Chan-Wha Kim, Eunice EunKyeong Kim, Gyochang Keum
A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC50 of 36nM and showed a submicromolar mean GI50 value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis...
November 23, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27909956/docking-and-three-dimensional-quantitative-structure-activity-relationship-analyses-of-imidazole-and-thiazolidine-derivatives-as-aurora-a-kinase-inhibitors
#3
Chaeuk Im
Aurora A kinase is involved in the inactivation of apoptosis leading to ovarian, breast, colon, and pancreatic cancers. Inhibitors of Aurora A kinase promote aberrant mitosis resulting in arrest at a pseudo G1 state to induce mitotic catastrophe, ultimately leading to apoptosis. In this study, ligand-based and docking-based three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses of imidazole and thiazolidine derivatives as potential Aurora A kinase inhibitors were performed. The results provided highly reliable and predictive 3D-QSAR comparative molecular similarity index analysis (CoMSIA) models with a cross-validated q(2) value of 0...
December 1, 2016: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/27881644/suppression-of-adenovirus-replication-by-cardiotonic-steroids
#4
Filomena Grosso, Peter Stoilov, Clifford Lingwood, Martha Brown, Alan Cochrane
: The dependence of adenovirus on the host pre-RNA splicing machinery for expression of its complete genome, potentially makes it vulnerable to modulators of RNA splicing, such as digoxin and digitoxin. Both drugs reduced the yield of four adenoviruses (HAdV-A31, B35, C5 and a species D conjunctivitis isolate) by at least 2- 3 logs by affecting one or more steps needed for genome replication. Immediate early E1A protein levels are unaffected by the drugs, but synthesis of the delayed protein E4orf6 and the major late capsid protein, hexon, are compromised...
November 23, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27874143/total-synthesis-of-natural-derivatives-and-artificial-analogs-of-13-oxyingenol-and-their-biological-evaluation
#5
Takayuki Ohyoshi, Yuki Tamura, Ichiro Hayakawa, Go Hirai, Yamato Miyazawa, Shota Funakubo, Mikiko Sodeoka, Hideo Kigoshi
We have established an efficient synthetic methodology for the 13-oxyingenol natural derivative (13-oxyingenol-13-dodecanoate-20-hexanoate), featuring a ring-closing olefin metathesis reaction for the "direct" construction of a highly strained inside-outside framework and a Mislow-Evans-type [2,3]-sigmatropic rearrangement for the stereoselective introduction of the hydroxy group at C5. We also synthesized artificial analogs of 13-oxyingenol and ingenol by using our synthetic strategy. In vitro activation assays of protein kinase C (PKC) α and δ revealed that the dodecanoyl group at O13 on 13-oxyingenol analogs had a significant role in PKCδ activation...
November 22, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27846451/sar-study-of-5-alkynyl-substituted-quinazolin-4-3h-ones-as-phosphoinositide-3-kinase-delta-pi3k%C3%AE-inhibitors
#6
Manman Wei, Xi Zhang, Xiang Wang, Zilan Song, Jian Ding, Ling-Hua Meng, Ao Zhang
PI3Kδ is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3Kδ has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3Kδ inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3Kδ (3.82 nM) and SU-DHL-6 cells (7...
January 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27810992/small-molecule-factor-d-inhibitors-selectively-block-the-alternative-pathway-of-complement-in-paroxysmal-nocturnal-hemoglobinuria-and-atypical-hemolytic-uremic-syndrome
#7
Xuan Yuan, Eleni Gavriilaki, Jane A Thanassi, Guangwei Yang, Andrea C Baines, Steven D Podos, Yongqing Huang, Mingjun Huang, Robert A Brodsky
Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome are diseases of excess activation of the alternative pathway of complement that are treated with eculizumab, a humanized monoclonal antibody against the terminal complement component C5. Eculizumab must be administered intravenously, and moreover some patients with paroxysmal nocturnal hemoglobinuria on eculizumab have symptomatic extravascular hemolysis, indicating an unmet need for additional therapeutic approaches. We report the activity of two novel small-molecule inhibitors of the alternative pathway component factor D using in vitro correlates of both paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome...
November 3, 2016: Haematologica
https://www.readbyqxmd.com/read/27810412/on-the-value-of-therapeutic-interventions-targeting-the-complement-system-in-acute-myocardial-infarction
#8
REVIEW
Reindert W Emmens, Diana Wouters, Sacha Zeerleder, S Marieke van Ham, Hans W M Niessen, Paul A J Krijnen
The complement system plays an important role in the inflammatory response subsequent to acute myocardial infarction (AMI). The aim of this study is to create a systematic overview of studies that have investigated therapeutic administration of complement inhibitors in both AMI animal models and human clinical trials. To enable extrapolation of observations from included animal studies toward post-AMI clinical trials, ex vivo studies on isolated hearts and proof-of-principle studies on inhibitor administration before experimental AMI induction were excluded...
October 14, 2016: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/27784126/monitoring-of-complement-activation-biomarkers-and-eculizumab-in-complement-mediated-renal-disorders
#9
C Wehling, O Amon, M Bommer, B Hoppe, K Kentouche, G Schalk, R Weimer, M Wiesener, B Hohenstein, B Tönshoff, R Büscher, H Fehrenbach, Ö-N Gök, M Kirschfink
Various complement-mediated renal disorders are treated currently with the complement inhibitor eculizumab. By blocking the cleavage of C5, this monoclonal antibody prevents cell damage caused by complement-mediated inflammation. We included 23 patients with atypical haemolytic uraemic syndrome (aHUS, n = 12), C3 glomerulopathies (C3G, n = 9) and acute antibody-mediated renal graft rejection (AMR, n = 2), treated with eculizumab in 12 hospitals in Germany. We explored the course of complement activation biomarkers and the benefit of therapeutic drug monitoring of eculizumab...
October 26, 2016: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/27735867/modulation-of-autophagy-by-a-thioxanthone-decreases-the-viability-of-melanoma-cells
#10
Raquel T Lima, Diana Sousa, Ana M Paiva, Andreia Palmeira, João Barbosa, Madalena Pedro, Madalena M Pinto, Emília Sousa, M Helena Vasconcelos
(1) Background: Our previous studies unveiled the hit thioxanthone TXA1 as an inhibitor of P-glycoprotein (drug efflux pump) and of human tumor cells growth, namely of melanoma cells. Since TXA1 is structurally similar to lucanthone (an autophagy inhibitor and apoptosis inducer) and to N(10)-substituted phenoxazines (isosteres of thioxanthones, and autophagy inducers), this study aimed at further assessing its cytotoxic mechanism and evaluating its potential as an autophagy modulator in A375-C5 melanoma cells; (2) Methods: Flow cytometry with propidium iodide (PI) for cell cycle profile analysis; Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry with Annexin V/PI labeling and Western blot for apoptosis analysis were conducted...
October 10, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27699905/freezing-the-dynamic-gap-for-selectivity-motion-based-design-of-inhibitors-of-the-shikimate-kinase-enzyme
#11
Verónica Prado, Emilio Lence, Paul Thompson, Alastair R Hawkins, Concepción González-Bello
Shikimate kinase (SK), the fifth enzyme of the aromatic amino acid biosynthesis, is a recognized target for antibiotic drug discovery. The potential of the distinct dynamic apolar gap, which isolates the natural substrate from the solvent environment for catalysis, and the motion of Mycobacterium tuberculosis and Helicobacter pylori SK enzymes, which was observed by molecular dynamics simulations, was explored for inhibition selectivity. The results of the biochemical and computational studies reveal that the incorporation of bulky groups at position C5 of 5-aminoshikimic acid and the natural substrate enhances the selectivity for the H...
October 4, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27692470/complement-activation-by-cholesterol-crystals-triggers-a-subsequent-cytokine-response
#12
Nathalie Niyonzima, Bente Halvorsen, Bjørnar Sporsheim, Peter Garred, Pål Aukrust, Tom Eirik Mollnes, Terje Espevik
In the host a diverse collection of endogenous danger signals is constantly generated consisting of waste material as protein aggregates or crystalline materials that are recognized and handled by soluble pattern recognition receptors and phagocytic cells of the innate immune system. These signals may under certain circumstances drive processes leading to adverse inflammation. One example is cholesterol crystals (CC) that accumulate in the vessel wall during early phases of atherogenesis and represent an important endogenous danger signal promoting inflammation...
September 28, 2016: Molecular Immunology
https://www.readbyqxmd.com/read/27638863/facin-a-double-edged-sword-of-the-emerging-periodontal-pathogen-filifactor-alocis-a-metabolic-enzyme-moonlighting-as-a-complement-inhibitor
#13
Monika Jusko, Beata Miedziak, David Ermert, Michal Magda, Ben C King, Ewa Bielecka, Kristian Riesbeck, Sigrun Eick, Jan Potempa, Anna M Blom
Periodontal disease is one of the most common inflammatory infectious diseases worldwide and it is associated with other syndromes, such as cardiovascular disease or rheumatoid arthritis. Recent advances in sequencing allowed for identification of novel periodontopathogens such as Gram-positive Filifactor alocis, but its virulence mechanisms remain largely unknown. We confirmed that F. alocis is a prevalent species in periodontitis patients, and we also observed strong correlation of this bacterium with clinical parameters, highlighting its role in the pathogenesis of the disease...
October 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27617501/c3-ch50-ratio-as-a-proposed-composite-marker-for-eculizumab-monitoring-in-atypical-hemolytic-uremic-syndrome-preliminary-results
#14
Kheir Eddine Kerboua, Fatma Haiba, Djamila Batouche
Treatment of atypical hemolytic uremic syndrome (aHUS) by the complement C5 inhibitor eculizumab (Soliris®) is highly effective but unfortunately, associated with an economic pressure on the health care systems even in high incomes countries. Despite spacing infusions has been proposed as the unique solution to minimize this economic impact, no reliable laboratory assays are available to tailor such therapy optimization. We aimed to propose and evaluate a complement composite marker for eculizumab efficacy monitoring in aHUS...
September 12, 2016: Journal of Immunoassay & Immunochemistry
https://www.readbyqxmd.com/read/27598771/pasylated-coversin-a-c5-specific-complement-inhibitor-with-extended-pharmacokinetics-shows-enhanced-anti-hemolytic-activity-in-vitro
#15
Nadine Kuhn, Christoph Q Schmidt, Martin Schlapschy, Arne Skerra
The Ornithodoros moubata Complement Inhibitor (OmCI) binds complement component 5 (C5) with high affinity and, thus, selectively prevents proteolytic activation of the terminal lytic complement pathway. A recombinant version of OmCI (also known as Coversin and rEV576) has proven efficacious in several animal models of complement-mediated diseases and successfully completed a phase Ia clinical trial. Coversin is a small 17 kDa lipocalin protein which has a very short plasma half-life if not bound to C5; therefore, the drug requires frequent dosing...
October 19, 2016: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/27573083/recommendations-for-serogroup-b-meningococcal-vaccine-for-persons-10-years-and-older
#16
(no author information available yet)
This policy statement provides recommendations for the prevention of serogroup B meningococcal disease through the use of 2 newly licensed serogroup B meningococcal vaccines: MenB-FHbp (Trumenba; Wyeth Pharmaceuticals, a subsidiary of Pfizer, Philadelphia, PA) and MenB-4C (Bexsero; Novartis Vaccines, Siena, Italy). Both vaccines are approved for use in persons 10 through 25 years of age. MenB-FHbp is licensed as a 2- or 3-dose series, and MenB-4C is licensed as a 2-dose series for all groups. Either vaccine is recommended for routine use in persons 10 years and older who are at increased risk of serogroup B meningococcal disease (category A recommendation)...
September 2016: Pediatrics
https://www.readbyqxmd.com/read/27558716/nanosecond-dynamics-of-g%C3%AE-i1-bound-to-nucleotides-or-ric-8a-a-g%C3%AE-chaperone-with-gef-activity
#17
Labe A Black, Celestine J Thomas, Gwendolyn N Nix, Michelle C Terwilliger, Stephen R Sprang, J B Alexander Ross
Resistance to Inhibitors of Cholinesterase A (Ric-8A) is a 60-kDa cytosolic protein that has chaperone and guanine nucleotide exchange (GEF) activity toward heterotrimeric G protein α subunits of the i, q, and 12/13 classes, catalyzing the release of GDP from Gα and subsequent binding of GTP. In the absence of GTP or GTP analogs, and subsequent to GDP release, Gα forms a stable nucleotide-free complex with Ric-8A. In this study, time-resolved fluorescence anisotropy measurements were employed to detect local motions of Gαi1 labeled at selected sites with Alexa 488 (C5) fluorescent dye (Ax) in the GDP, GTPγS (collectively, GXP), and Ric-8A-bound states...
August 23, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27536669/complement-in-lupus-nephritis-new-perspectives
#18
REVIEW
Lihua Bao, Patrick N Cunningham, Richard J Quigg
BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder caused by loss of tolerance to self-antigens, the production of autoantibodies and deposition of complement-fixing immune complexes (ICs) in injured tissues. SLE is characterized by a wide range of clinical manifestations and targeted organs, with lupus nephritis being one of the most serious complications. The complement system consists of three pathways and is tightly controlled by a set of regulatory proteins to prevent injudicious complement activation on host tissue...
September 2015: Kidney Diseases
https://www.readbyqxmd.com/read/27530289/synthesis-and-activity-of-benzimidazole-1-3-dioxide-inhibitors-of-separase
#19
Ha T Do, Nenggang Zhang, Debananda Pati, Scott R Gilbertson
Due to the oncogenic activity of cohesin protease, separase in human cancer cells, modulation of separase enzymatic activity could constitute a new therapeutic strategy for targeting resistant, separase-overexpressing aneuploid tumors. Herein, we report the synthesis, structural information, and structure-activity relationship (SAR) of separase inhibitors based on modification of the lead molecule 2,2-dimethyl-5-nitro-2H-benzimidazole-1,3-dioxide, named Sepin-1, (1) identified from a high-throughput-screen...
September 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27509843/stratification-of-responders-towards-eculizumab-using-a-structural-epitope-mapping-strategy
#20
Anna-Luisa Volk, Francis Jingxin Hu, Magnus M Berglund, Erik Nordling, Patrik Strömberg, Mathias Uhlen, Johan Rockberg
The complement component 5 (C5)-binding antibody eculizumab is used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS). As recently reported there is a need for a precise classification of eculizumab responsive patients to allow for a safe and cost-effective treatment. To allow for such stratification, knowledge of the precise binding site of the drug on its target is crucial. Using a structural epitope mapping strategy based on bacterial surface display, flow cytometric sorting and validation via haemolytic activity testing, we identified six residues essential for binding of eculizumab to C5...
2016: Scientific Reports
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