Factor D Catalog Number
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WO 2016/147053 Al 22 September 2016 (22.09.2016) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/147053 Al 22 September 2016 (22.09.2016) P O P C T (51) International Patent Classification: (71) Applicant: RESVERLOGIX CORP. [CA/CA]; 300, A61K 31/551 (2006.01) A61P 37/02 (2006.01) 4820 Richard Road Sw, Calgary, AB, T3E 6L1 (CA). A61K 31/517 (2006.01) C07D 239/91 (2006.01) (72) Inventors: WASIAK, Sylwia; 431 Whispering Water (21) International Application Number: Trail, Calgary, AB, T3Z 3V1 (CA). KULIKOWSKI, PCT/IB20 16/000443 Ewelina, B.; 31100 Swift Creek Terrace, Calgary, AB, T3Z 0B7 (CA). HALLIDAY, Christopher, R.A.; 403 (22) International Filing Date: 138-18th Avenue SE, Calgary, AB, T2G 5P9 (CA). GIL- 10 March 2016 (10.03.2016) HAM, Dean; 249 Scenic View Close NW, Calgary, AB, (25) Filing Language: English T3L 1Y5 (CA). (26) Publication Language: English (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (30) Priority Data: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 62/132,572 13 March 2015 (13.03.2015) US BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 62/264,768 8 December 2015 (08. 12.2015) US DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, [Continued on nextpage] (54) Title: COMPOSITIONS AND THERAPEUTIC METHODS FOR THE TREATMENT OF COMPLEMENT-ASSOCIATED DISEASES (57) Abstract: The invention comprises methods of modulating the complement cascade in a mammal and for treating and/or preventing diseases and disorders as sociated with the complement pathway by administering a compound of Formula I or Formula II, such as, for example, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)- 5,7-dimethoxyquinazolin-4(3H)-one or a pharmaceutically acceptable salt thereof. -
Properdin Factor D: Effects on Thrombin-Induced Platelet Aggregation
Properdin factor D: effects on thrombin-induced platelet aggregation. A E Davis 3rd, D M Kenney J Clin Invest. 1979;64(3):721-728. https://doi.org/10.1172/JCI109515. Research Article Factor D, when preincubated with platelet suspensions, at concentrations as low as 1.2 micrograms/ml, inhibited thrombin-induced platelet aggregation. No inhibition of collagen or arachidonic acid-induced platelet aggregation was found. Inhibition occurred, but to a lesser extent, when thrombin and factor D were added to platelets at the same time. No inhibition occurred when factor D was added after thrombin. Thrombin was able to overcome inhibition by factor D by increasing its concentration. Diisopropyl-phosphorofluoridate-inactivated factor D also inhibited thrombin-induced platelet aggregation so that enzymatic activity of factor D was not required for inhibition. Factor D absorbed with hirudin coupled to Sepharose 6B showed no decrease in inhibitory capacity. 125I-Factor D bound to platelets in a manner suggesting an equilibrium reaction similar to thrombin. At low factor D input, binding was linear, whereas at higher input, binding began to approach saturation. Binding of 125I-labeled thrombin to platelets was inhibited by factor D. Analysis of these data show that factor D does not alter the total number of thrombin molecules which bind to the platelet surface at saturation. However, the dissociation constant for thrombin is altered from 2.78 to 6.90 nM in the presence of factor D (20 micrograms/ml). Factor D is thus a competitive inhibitor of thrombin binding, although the affinity of factor D for the platelet thrombin receptor is much less […] Find the latest version: https://jci.me/109515/pdf Properdin Factor D EFFECTS ON THROMBIN-INDUCED PLATELET AGGREGATION ALVIN E. -
Crystal Structure of Prethrombin-1
Crystal structure of prethrombin-1 Zhiwei Chen, Leslie A. Pelc, and Enrico Di Cera1 Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104 Edited by Robert M. Stroud, University of California, San Francisco, CA, and approved September 24, 2010 (received for review July 14, 2010) Prothrombin is the zymogen precursor of the clotting enzyme thrombin, which is generated by two sequential cleavages at R271 and R320 by the prothrombinase complex. The structure of prothrombin is currently unknown. Prethrombin-1 differs from pro- thrombin for the absence of 155 residues in the N-terminal domain and is composed of a single polypeptide chain containing fragment 2 (residues 156–271), A chain (residues 272–320), and B chain (re- sidues 321–579). The X-ray crystal structure of prethrombin-1 solved at 2.2-Å resolution shows an overall conformation signifi- cantly different (rmsd ¼ 3.6 Å) from that of its active form meizo- thrombin desF1 carrying a cleavage at R320. Fragment 2 is rotated around the y axis by 29° and makes only few contacts with the B chain. In the B chain, the oxyanion hole is disrupted due to absence of the I16-D194 ion pair and the Naþ binding site and adjacent primary specificity pocket are highly perturbed. A remarkable feature of the structure is that the autolysis loop assumes a helical conformation enabling W148 and W215, located 17 Å apart in mei- zothrombin desF1, to come within 3.3 Å of each other and comple- tely occlude access to the active site. -
Factor B, the Complement Alternative Pathway Serine Proteinase, Is a Major Constitutive Protein Synthesized and Secreted by Resident and Elicited Mouse Macrophages
FACTOR B, THE COMPLEMENT ALTERNATIVE PATHWAY SERINE PROTEINASE, IS A MAJOR CONSTITUTIVE PROTEIN SYNTHESIZED AND SECRETED BY RESIDENT AND ELICITED MOUSE MACROPHAGES BY JOHN S. SUNDSMO, JENNIE R. CHIN,* RUTH A. PAPIN, DARYL S. FAIR, AND ZENA WERB* From the Department of Molecular Immunology, Scripps Clinic and Research Foundation, La Jolla, California 92037; and the *Laboratory of Radiobiology and Environmental Health, and Department of Anatomy, University of California, San Francisco, California 94143 Mononuclear phagocytes have been increasingly recognized as a source of many of the complement proteins (1, 2). Activities constituting the intact com- plement alternative pathway in serum (factor B, factor D, C3, and properdin) (3-8), as well as the regulatory proteins, factors H and I (5, 8), are produced by mouse peritoneal macrophages and human peripheral blood monocytes. Factors C2 and C4 are also synthesized by mononuclear phagocytes (1, 2, 5, 9-11). Factor B, a glycoprotein of Mr ~0.3,000 that plays a central role in the alternative pathway of complement activation (12, 13), is closely associated with the immune response as a class III gene product of the major histocompatibility complex in mice (14, 15), guinea pigs (16), and humans (17). Activated factor B (Bb, Mr ~60,000) serves as a migration inhibiting factor (18), inducing macro- phage and monocyte spreading (19, 20) and possibly stimulating cytotoxic (21, 22) and bacteriocidai activities (23, 24) of monocytes in vitro. The hemolytic activity of factor B produced by resident mouse peritoneal macrophages (3, 6) increases linearly during 72-96 h in culture, and its synthesis is regulated by lipopolysaccharide (LPS) 1 (24). -
Factor B Catalog Number
Name: Factor B Catalog Number: A135 Sizes Available: 250 µg/vial Concentration: 1.0 mg/mL (see Certificate of Analysis for actual concentration) Form: Frozen liquid Activity: >90% versus normal human serum standard. Purity: >95% by SDS-PAGE Buffer: 10 mM Sodium phosphate, 145 mM NaCl, pH 7.2 Molecular weight: 93,000 Da (single chain) Extinction Coeff.: A280 nm = 1.27 at 1.0 mg/mL Preservative: None, 0.22 µm filtered Storage: -70oC or below. Avoid repeated freeze/thaw. Source: Normal human serum (shown by certified tests to be negative for HBsAg and for antibodies to HCV, HIV-1 and HIV-II). Precautions: Use normal precautions for handling human blood products. Origin: Manufactured in the USA. General Description Complement factor B (fB) is purified from normal human serum. Complement factor B is a glycosylated protein composed of a single 93,000 Da polypeptide chain. It is an essential component of the alternative pathway of complement activation and is found in plasma at approximately 200 µg/mL. In the presence of Mg++ factor B binds to C3b and the C3b,B complex can be activated by factor D, a serine protease that circulates as an active trypsin-like serine protease. Cleavage of factor B by factor D causes the release of the Ba fragment (33,000 Da) and leaves the 60,000 Bb fragment bound to C3b. This Bb subunit is a serine protease. C3b,Bb is called a C3 and a C5 convertase because it converts both of these proteins to their active forms by cleaving off the small peptides C3a and C5a, respectively (Morikis, D. -
Complement Activation in Factor D-Deficient Mice
Complement activation in factor D-deficient mice Yuanyuan Xu*†, Minghe Ma‡, Gregory C. Ippolito*, Harry W. Schroeder, Jr.*, Michael C. Carroll‡, and John E. Volanakis*§ *Department of Medicine, University of Alabama, Birmingham, AL 35294; ‡Department of Pathology, Harvard Medical School, Boston, MA 02138; and §Biomedical Sciences Research Center ‘‘A. Fleming,’’ Vari 166 72, Greece Edited by Douglas T. Fearon, University of Cambridge, Cambridge, United Kingdom, and approved October 18, 2001 (received for review August 15, 2001) To assess the contribution of the alternative pathway in comple- mice. The results indicate that factor D is indispensable for ment activation and host defense and its possible role in the complement activation through the AP and that it plays a regulation of systemic energy balance in vivo, factor D-deficient significant role in opsonization of bacteria by ‘‘natural’’ IgM mice were generated by gene targeting. The mutant mice have no antibody. It is also shown that factor D does not play a major role apparent abnormality in development and their body weights are in fat metabolism. Interestingly, the data revealed a unique mode similar to those of factor D-sufficient littermates. Complement of factor B activation, which provides valuable insights into the activation could not be initiated in the serum of deficient mice by mechanism of AP activation. the alternative pathway activators rabbit erythrocytes and zymo- san. Surprisingly, injection of cobra venom factor (CVF) caused a Materials and Methods profound and reproducible reduction in serum C3 levels, whereas, Generation of Factor D-Deficient Mice. A gene targeting vector, as expected, there was no C3 reduction in factor B-deficient mice Adn͞TK, was constructed (9) on the backbone of pBluescript treated similarly. -
Innate Immunity: the Inside Story on Complement Activation
RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 31 December 2013; doi:10.1038/nri3603 INNATE IMMUNITY The inside story on complement activation The evolutionarily ancient comple- inconsistent with de novo protein — the production of interferon-γ ment system might have started life production, so the authors looked (IFNγ) and interleukin-17 was sig- as an intracellular activation pathway for a potential role of endogenous nificantly decreased but could be par- rather than as a liver-derived serum proteases. They showed that rest- tially rescued by the addition of C3a. effector cascade. Other recent studies ing human T cells express mRNA Cytokine production was not affected have suggested the importance of encoding cathepsin L (CTSL), and in serum-free medium or in the T cell-derived local complement acti- that CTSL cleaves C3 into biologi- presence of a C3 convertase inhibitor, vation in the autocrine stimulation of cally active C3a and C3b fragments which shows that the CTSL-mediated T helper 1 (T 1) cell responses, but in vitro. C3 and CTSL were found to C3 activation pathway is sufficient H intracellular Claudia Kemper, John Atkinson and be colocalized in resting T cells in for autocrine C3aR-induced T cell colleagues are the first to show that C3a the endoplasmic reticulum (ER) and effector function in humans. the C3 activation products C3a and generation ER-derived secretory vesicles. The in vivo relevance of this C3b can be generated intracellularly … is both Intracellular C3a was detected in pathway was shown in synovial fluid in human CD4+ T cells. resting T cells, and the increase in CD4+ T cells from patients with juve- Activation of mouse T cells is upregulated intracellular C3a levels observed after nile idiopathic arthritis. -
A Family with Complement Factor D Deficiency
A family with complement factor D deficiency Douwe H. Biesma,1 André J. Hannema,2 Heleen van Velzen-Blad,3 Leontine Mulder,3 Rob van Zwieten,2 Irma Kluijt,4 and Dirk Roos2,5 1Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands 2Central Laboratory of the Netherlands Blood Transfusion Service, Amsterdam, The Netherlands 3Department of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein, The Netherlands 4Department of Clinical Genetics, and 5Laboratory for Experimental and Clinical Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Address correspondence to: Douwe H. Biesma, Department of Internal Medicine, St. Antonius Hospital, PO Box 2500, 3430 EM Nieuwegein, The Netherlands. Phone: 31-30-6099111; Fax: 31-30-6056357; E-mail: [email protected]. Received for publication December 15, 2000, and accepted in revised form June 11, 2001. A complement factor D deficiency was found in a young woman who had experienced a serious Neis- seria meningitidis infection, in a deceased family member with a history of meningitis, and in three rel- atives without a history of serious infections. The patient and these three relatives showed a normal activity of the classical complement pathway, but a very low activity of the alternative complement pathway and a very low capacity to opsonize Escherichia coli and N. meningitidis (isolated from the patient) for phagocytosis by normal human neutrophils. The alternative pathway-dependent hemolytic activity and the opsonizing capacity of these sera were restored by addition of purified fac- tor D. The family had a high degree of consanguinity, and several other family members exhibited decreased levels of factor D. -
Targeting of Mannan-Binding Lectin-Associated Serine Protease-2 Confers Protection from Myocardial and Gastrointestinal Ischemia/Reperfusion Injury
Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury Wilhelm J. Schwaeblea,1, Nicholas J. Lyncha, James E. Clarkb, Michael Marberb, Nilesh J. Samanic, Youssif Mohammed Alia,d, Thomas Dudlere, Brian Parente, Karl Lhottaf, Russell Wallisa, Conrad A. Farrarg, Steven Sacksg, Haekyung Leeh, Ming Zhangh, Daisuke Iwakii, Minoru Takahashii, Teizo Fujitai, Clark E. Tedforde, and Cordula M. Stovera Departments of aInfection, Immunity, and Inflammation and cCardiovascular Sciences, University of Leicester, Leicester LE1 9HN, United Kingdom; bBritish Heart Foundation Centre and gMedical Research Council Centre for Transplantation and National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust, King’s College London, London SE1 9RT, United Kingdom; dFaculty of Pharmacy, Department of Microbiology, University of Mansoura, Mansoura 35516, Egypt; eOmeros Corporation, Seattle, WA 98101; fLandeskrankenhaus Feldkirch, 6807 Feldkirch, Austria; hDepartment of Anesthesiology, State University of New York-Downstate Medical Center, New York, NY 11203; and iDepartment of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan Edited* by Douglas T. Fearon, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, and approved March 16, 2011 (received for review February 1, 2011) Complement research experienced a renaissance with the discovery aberrant glycosylation -
Strategies of Targeting Alternative and Lectin Pathway Components in Complement- Mediated Diseases
REVIEW published: 08 August 2018 doi: 10.3389/fimmu.2018.01851 Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement- Mediated Diseases József Dobó, Andrea Kocsis and Péter Gál* Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary The complement system has moved into the focus of drug development efforts in the last decade, since its inappropriate or uncontrolled activation has been recognized in many diseases. Some of them are primarily complement-mediated rare diseases, such as paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis, and atypical hemolytic uremic syndrome. Complement also plays a role in various multifactorial diseases that affect millions of people worldwide, such as ischemia reperfusion injury (myocardial infarction, stroke), age-related macular degeneration, and several neurodegenerative disorders. In this review, we summarize the potential advantages of targeting various Edited by: complement proteins with special emphasis on the components of the lectin (LP) and Nicole Thielens, UMR5075 Institut de Biologie the alternative pathways (AP). The serine proteases (MASP-1/2/3, factor D, factor B), Structurale (IBS), France which are responsible for the activation of the cascade, are straightforward targets of Reviewed by: inhibition, but the pattern recognition molecules (mannose-binding lectin, other collectins, Cordula M. Stover, and ficolins), the regulatory components (factor H, factor I, properdin), and C3 are also University of Leicester, United Kingdom subjects of drug development. Recent discoveries about cross-talks between the LP Maciej Cedzynski, and AP offer new approaches for clinical intervention. Mannan-binding lectin-associated Institute for Medical Biology (PAN), Poland serine proteases (MASPs) are not just responsible for LP activation, but they are also Christian Drouet, indispensable for efficient AP activation. -
Role of Complement in Diabetes
This is a repository copy of Role of complement in diabetes. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/151783/ Version: Accepted Version Article: Ajjan, RA and Schroeder, V (2019) Role of complement in diabetes. Molecular Immunology, 114. pp. 270-277. ISSN 0161-5890 https://doi.org/10.1016/j.molimm.2019.07.031 (c) 2019, Elsevier Ltd. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/ Reuse This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) licence. This licence only allows you to download this work and share it with others as long as you credit the authors, but you can’t change the article in any way or use it commercially. More information and the full terms of the licence here: https://creativecommons.org/licenses/ Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Molecular Immunology, Special Issue EMCHD 2019 Review Article Role of Complement in Diabetes Ramzi A. Ajjan a, Verena Schroeder b* a Leeds Institute for Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom b Experimental Haemostasis Group, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland * Corresponding author: Verena Schroeder Experimental Haemostasis Group Department for BioMedical Research (DBMR) University of Bern Murtenstrasse 40 3008 Bern Switzerland Tel.: +41 31 632 9618 E-mail: [email protected] 1 Abstract Accumulating evidence suggests a role for the complement system in the pathogenesis of diabetes and the vascular complications that characterise this condition. -
Complement in Tumourigenesis and the Response to Cancer Therapy
cancers Review Complement in Tumourigenesis and the Response to Cancer Therapy Rebecca M. O’Brien 1,2, Aoife Cannon 1, John V. Reynolds 1, Joanne Lysaght 1,2 and Niamh Lynam-Lennon 1,* 1 Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland; [email protected] (R.M.O.); [email protected] (A.C.); [email protected] (J.V.R.); [email protected] (J.L.) 2 Cancer Immunology and Immunotherapy Group, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin and St. James’s Hospital, Dublin 8, Ireland * Correspondence: [email protected] Simple Summary: Increasing evidence supports a role for complement in the development of cancer and the response to cancer treatments. Dysregulated complement expression within the tumour microenvironment has been linked to the suppression of anti-tumour immunity and poor clinical outcomes. Complement signals have been demonstrated to alter the immune milieu, promote proliferation and facilitate metastasis. Targeting complement signalling in combination with current treatments may have the potential to achieve improved control of tumour growth. Abstract: In recent years, our knowledge of the complement system beyond innate immunity has progressed significantly. A modern understanding is that the complement system has a multifaceted role in malignancy, impacting carcinogenesis, the acquisition of a metastatic phenotype and response to therapies. The ability of local immune cells to produce and respond to complement components has provided valuable insights into their regulation, and the subsequent remodeling of the tumour Citation: O’Brien, R.M.; Cannon, A.; Reynolds, J.V.; Lysaght, J.; microenvironment.