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David R Clemmons - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of insulin-like growth factor binding protein 5 proteolysis in articular cartilage and joint fluid results in enhanced concentrations of insulin-like growth factor 1 and is associated with improved osteoarthritis
Arthritis & Rheumatism, 2002Co-Authors: David R Clemmons, Walker H Busby, Aaron Garmong, Duane R. Schultz, David S. Howell, Roy D. Altman, Robert W. KarrAbstract:OBJECTIVE: The Complement Component C1s is present in dog joint fluid in an activated state. Since C1s degrades insulin-like growth factor binding protein 5 (IGFBP-5), we undertook to determine whether inhibiting C1s in joint fluid would result in an increase in the amount of intact IGFBP-5 and IGF-1 in cartilage and joint fluid, and whether C1s inhibition would be associated with a reduction in cartilage destruction during the development of osteoarthritis (OA). METHODS: Twenty-two dogs were randomized to 3 treatment groups. All dogs underwent anterior cruciate ligament transection and were exercised. Dogs received 1 of 3 treatments: buffer alone (controls; n = 6); PB-145, a peptide derived from the sequence of antithrombin III (n = 9); and pentosan polysulfate (PPS; n = 7). PB-145 or saline was injected into the joint space 3 times per week for 3 weeks. PPS was injected intramuscularly weekly for 3 weeks. RESULTS: Joint histology showed preservation of chondrocytes and a smooth joint surface in the animals treated with PB-145 and PPS. Mankin scoring showed statistically significant reductions in joint destruction with PB-145 and PPS treatments (P < 0.01) compared with buffer control. Mean active collagenase concentrations were decreased by these two treatments. Immunoblotting of joint fluid showed that both treatments increased concentrations of intact IGFBP-5. Direct analysis of IGFBP-3 and IGFBP-5 protease activity showed that IGFBP-5 was degraded more rapidly and that PB-145 and PPS inhibited the degradation of both proteins. Total IGF-1 concentrations in joint fluid were increased 5.6-5.8-fold by these two treatments. Analysis showed that C1s was being activated in joint fluid and that its activation was inhibited by the addition of PB-145 or PPS. CONCLUSION: The findings suggest that direct inhibition of the serine protease C1s results in increased concentrations of intact IGFBP-5 and that proteolysis of IGFBP-3 is also inhibited, probably by the inhibition of some other protease. This increase in concentrations of intact IGFBP-3 and IGFBP-5 leads to an increase in IGF-1 which is associated with an improvement in joint architecture during the development of OA.
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the Complement Component C1s is the protease that accounts for cleavage of insulin like growth factor binding protein 5 in fibroblast medium
Journal of Biological Chemistry, 2000Co-Authors: Walker H Busby, Anna Moralez, Christine Smith, Michael Jennings, David R ClemmonsAbstract:Abstract Cultured fibroblasts secrete an 88-kDa serine protease that cleaves insulin-like growth factor binding protein-5 (IGFBP-5). Because IGFBP-5 has been shown to regulate IGF-I actions, understanding the chemical identity and regulation of this protease is important for understanding how IGF-I stimulates anabolic functions. The protease was purified from human fibroblast-conditioned medium by hydrophobic interaction, lectin affinity, and heparin Sepharose affinity chromatography followed by SDS-polyacrylamide gel electrophoresis. An 88-kDa band was excised and digested with lysyl-endopeptidase. Sequencing of the high pressure liquid chromatography-purified peptides yielded the Complement Components C1r and C1s. To confirm that C1r/C1s accounted for the proteolytic activity in the medium, immunoaffinity chromatography was performed. Most of the protease activity adhered to the column, and the eluant was fully active in cleaving IGFBP-5. SDS-polyacrylamide gel electrophoresis with silver staining showed two bands, and IGFBP-5 zymography showed a single 88-kDa band. Amino acid sequencing confirmed that the 88-kDa band contained only C1r and C1s. C1r in the fibroblast medium underwent autoactivation, and the activated form cleaved C1s. C1s purified from the conditioned medium cleaved C4, a naturally occurring substrate. The purified protease cleaved IGFBP-5 but had no activity against IGFBP-1 through -4. C1 inhibitor, a protein known to inhibit activated C1s, was shown to inhibit the cleavage of IGFBP-5 by the protease in the conditioned medium. In summary, human fibroblasts secrete C1r and C1s that actively cleave IGFBP-5. The findings define a mechanism for cleaving IGFBP-5 in the culture medium, thus allowing release of IGF-I to cell surface receptors.
Roger F Bone - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of polyethylene glycol modified biphenylsulfonyl thiophene carboxamidine inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Nalin Subasinghe, Jeremy M Travins, Shelley K Ballentine, Ehab Khalil, Heather Rae Hufnagel, Roger F Bone, Richard M Soll, Carl Crysler, Kristi A Leonard, Nisha NinanAbstract:Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical Complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
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biphenylsulfonyl thiophene carboxamidine inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Jeremy M Travins, Hui Huang, Shelley K Ballentine, Ehab Khalil, Heather Rae Hufnagel, Joan Gushue, Kristi Leonard, Roger F Bone, Richard M Soll, Renee L DesjarlaisAbstract:Abstract Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the Complement cascade provides several protein targets for potential therapeutic intervention only two Complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of Complement is described.
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a novel series of arylsulfonylthiophene 2 carboxamidine inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Nalin Subasinghe, Jeremy M Travins, Hui Huang, Shelley K Ballentine, Ehab Khalil, Heather Rae Hufnagel, Roger F Bone, Renee L Desjarlais, Juan J Marugan, Carl CryslerAbstract:Abstract Inhibiting the classical pathway of Complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia–reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a K i of 10 nM and >1000-fold selectivity over uPA, tPA, FX a , thrombin, and plasmin.
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a novel series of potent and selective small molecule inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Nalin Subasinghe, Ehab Khalil, Roger F Bone, Richard M Soll, Renee L Desjarlais, Carl R Illig, Jonathan M Rudolph, Scott I Klein, John C Spurlino, Carl CryslerAbstract:Abstract Activation of the classical pathway of Complement has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury and acute transplant rejection. The trypsin-like serine protease C1s represents a pivotal upstream point of control in the classical pathway of Complement activation and is therefore likely to be a useful target in the therapeutic intervention of these disease states. A series of thiopheneamidine-based inhibitors of C1s has been optimized to give a 70 nM inhibitor that inhibits the classical pathway of Complement activation in vitro.
Ehab Khalil - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of polyethylene glycol modified biphenylsulfonyl thiophene carboxamidine inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Nalin Subasinghe, Jeremy M Travins, Shelley K Ballentine, Ehab Khalil, Heather Rae Hufnagel, Roger F Bone, Richard M Soll, Carl Crysler, Kristi A Leonard, Nisha NinanAbstract:Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical Complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
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biphenylsulfonyl thiophene carboxamidine inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Jeremy M Travins, Hui Huang, Shelley K Ballentine, Ehab Khalil, Heather Rae Hufnagel, Joan Gushue, Kristi Leonard, Roger F Bone, Richard M Soll, Renee L DesjarlaisAbstract:Abstract Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the Complement cascade provides several protein targets for potential therapeutic intervention only two Complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of Complement is described.
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a novel series of arylsulfonylthiophene 2 carboxamidine inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Nalin Subasinghe, Jeremy M Travins, Hui Huang, Shelley K Ballentine, Ehab Khalil, Heather Rae Hufnagel, Roger F Bone, Renee L Desjarlais, Juan J Marugan, Carl CryslerAbstract:Abstract Inhibiting the classical pathway of Complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia–reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a K i of 10 nM and >1000-fold selectivity over uPA, tPA, FX a , thrombin, and plasmin.
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a novel series of potent and selective small molecule inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Nalin Subasinghe, Ehab Khalil, Roger F Bone, Richard M Soll, Renee L Desjarlais, Carl R Illig, Jonathan M Rudolph, Scott I Klein, John C Spurlino, Carl CryslerAbstract:Abstract Activation of the classical pathway of Complement has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury and acute transplant rejection. The trypsin-like serine protease C1s represents a pivotal upstream point of control in the classical pathway of Complement activation and is therefore likely to be a useful target in the therapeutic intervention of these disease states. A series of thiopheneamidine-based inhibitors of C1s has been optimized to give a 70 nM inhibitor that inhibits the classical pathway of Complement activation in vitro.
Nalin Subasinghe - One of the best experts on this subject based on the ideXlab platform.
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design and synthesis of polyethylene glycol modified biphenylsulfonyl thiophene carboxamidine inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Nalin Subasinghe, Jeremy M Travins, Shelley K Ballentine, Ehab Khalil, Heather Rae Hufnagel, Roger F Bone, Richard M Soll, Carl Crysler, Kristi A Leonard, Nisha NinanAbstract:Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical Complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
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a novel series of arylsulfonylthiophene 2 carboxamidine inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: Nalin Subasinghe, Jeremy M Travins, Hui Huang, Shelley K Ballentine, Ehab Khalil, Heather Rae Hufnagel, Roger F Bone, Renee L Desjarlais, Juan J Marugan, Carl CryslerAbstract:Abstract Inhibiting the classical pathway of Complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia–reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a K i of 10 nM and >1000-fold selectivity over uPA, tPA, FX a , thrombin, and plasmin.
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a novel series of potent and selective small molecule inhibitors of the Complement Component C1s
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Nalin Subasinghe, Ehab Khalil, Roger F Bone, Richard M Soll, Renee L Desjarlais, Carl R Illig, Jonathan M Rudolph, Scott I Klein, John C Spurlino, Carl CryslerAbstract:Abstract Activation of the classical pathway of Complement has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury and acute transplant rejection. The trypsin-like serine protease C1s represents a pivotal upstream point of control in the classical pathway of Complement activation and is therefore likely to be a useful target in the therapeutic intervention of these disease states. A series of thiopheneamidine-based inhibitors of C1s has been optimized to give a 70 nM inhibitor that inhibits the classical pathway of Complement activation in vitro.
Mogens Holst Nissen - One of the best experts on this subject based on the ideXlab platform.
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limited proteolysis of β2 microglobulin at lys 58 by Complement Component C1s
FEBS Journal, 1990Co-Authors: Mogens Holst Nissen, Peter Roepstorff, Lars Thim, Bryan Dunbar, John E FothergillAbstract:We have now demonstrated that activated Complement Component C1s cleaves β2-microglobulin at the position identical to that at which β2-microglobulin is cleaved in serum of patients suffering from lung cancer. The main cleavage is in the disulphide loop C-terminal to Lys-58, generating a modified form of β2-microglobulin with a two-chain structure. The C-terminal Lys-58 in the A chain is highly susceptible to removal by a carboxypeptidase-B-like activity causing the formation of des-Lys58 -β2-microglobulin. This is the first demonstration of a non-Complement protein substrate for the proteolytic activity of C1s. The C1s-induced cleavage of β2-microglobulin can be inhibited in the presence of C1 esterase inhibitor, demonstrating a regulatory function of C1 esterase inhibitor in the C1s-induced cleavage of β2-microglobulin.
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proteolysis of the heavy chain of major histocompatibility complex class i antigens by Complement Component C1s
Biochimica et Biophysica Acta, 1990Co-Authors: Hakan Eriksson, Mogens Holst NissenAbstract:Abstract The major histocompatibility complex (MHC) class I antigens contain a light chain β2-microglobulin, non-covalently associated to the transmembrane heavy α-chain carrying the allotypic determinants. Since the C1q Complement Component is known to associate with β2-microglobulin, and we recently found that activated C1s Complement was capable of cleaving β2-microglobulin, we decided to investigate the proteolytic activity of C1 Complement towards the heavy chain of class I antigens. Our results demonstrate that human C1s Complement cleaves the heavy chain of human class I antigens into at least two fragments, with apparent molecular weights of 22 000 and 24 000 g/ mol on sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), under both reducing and non-reducing conditions. The cleavage of the heavy chain is inhibited by the presence of C1 esterase inhibitor. The molecular weights of the fragments are in agreement with the cleavage located in the area between the disulphide loops of the α2-andα3-domains of the heavy chain. In addition human C1s Complement is able to cleave H-2 antigens from mouse in a similar fashion but not rat MHC class I antigen or mouse MHC class II antigen (I-Ad). Mouse MHC class I antigen-specific determinants could also be detected in supernatant from mouse spleen cells incubated with C1r and C1s. These results indicate the presence in the body fluids of a non-membrane-bound soluble form of the α1andα2-domains which represent the binding site for atnigenic peptide.