Inhibition of endotoxin response by synthetic TLR4 antagonists

Current Topics in Medicinal Chemistry

Volumn 4, Issue 11, 2004, Pages 1147-1171

  Hawkins, Lynn D ^a   Christ, William J ^b   Rossignol, Daniel P ^c  

^a EISAI RESEARCH INSTITUTE   (United States)

^b Ancora Pharmaceuticals   (United States)

^c EISAI INC   (United States)

Author keywords

Antagonist; E5564; Endotoxin; Gram negative; Lipopolysaccharide; Sepsis; Septic shock

Indexed keywords

1 ALKYL 2 ACETYLGLYCEROPHOSPHOCHOLINE ESTERASE; ACTIVATED PROTEIN C; BACTERIUM LIPOPOLYSACCHARIDE; BRADYKININ ANTAGONIST; DROTRECOGIN; E 5531; E 5564; ENDOTOXIN; INTERLEUKIN 1 RECEPTOR BLOCKING AGENT; LIPID A; LIPID A DERIVATIVE; LIPID X; LIPOPOLYSACCHARIDE; NITRIC OXIDE SYNTHASE INHIBITOR; PLACEBO; POLYMYXIN B; PROTEIN KINASE INHIBITOR; PROTEINASE INHIBITOR; THALIDOMIDE; TOLL LIKE RECEPTOR 4; TUMOR NECROSIS FACTOR ANTIBODY; UNCLASSIFIED DRUG;

BACTERIAL STRAIN; BACTERIAL VIRULENCE; CELL ACTIVATION; CLINICAL TRIAL; DEATH; DRUG ACTIVITY; DRUG BLOOD LEVEL; DRUG DESIGN; DRUG DETERMINATION; DRUG EFFICACY; DRUG POTENCY; DRUG RESEARCH; DRUG SAFETY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; EX VIVO STUDY; EXPERIMENTAL MODEL; FEVER; GRAM NEGATIVE BACTERIUM; GRAM NEGATIVE SEPSIS; HUMAN; IMMUNOCOMPETENT CELL; IN VITRO STUDY; IN VIVO STUDY; INHIBITION KINETICS; MOUSE; NONHUMAN; OUTER MEMBRANE; PATHOGENESIS; PHASE 1 CLINICAL TRIAL; PHLEBITIS; RAT; REVIEW; SEPTIC SHOCK; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

ANIMALS; DRUG DESIGN; ENDOTOXINS; HUMANS; LIPOPOLYSACCHARIDES; MEMBRANE GLYCOPROTEINS; RECEPTORS, CELL SURFACE; SEPSIS; TOLL-LIKE RECEPTOR 4; TOLL-LIKE RECEPTORS;

EID: 3142713223     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/1568026043388123     Document Type: Review

References (100)

1. Bone, R. C. Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome) [see comments]. JAMA 1992, 268, 3452-3455.
2. Bernard, G. R.; Wheeler, A. P.; Russell, J. A.; Schein. R.; Summer, W. R.; Steinberg, K. P.; Fulkerson, W. J.; Wright, P. E.; Christman, B. W.; Dupont, W. D.; Higgins, S. B.; Swindell, B. B. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group [see comments]. N. Engl. J. Med. 1997, 336, 912-918.
3. Vincent, J. L.; Sun, Q.; Dubois, M. J. Clinical trials of immunomodulatory therapies in severe sepsis and septic shock. Clin. Infect. Dis. 2002, 34, 1084-1093.
4. Ulmer, A. J.; Rietschel, E. T.; Zahringer, U.; Heine, H. Lipopolysaccharide: Structure, Bioactivity, Receptors and Signal Transduction. Trends in Glycosciences and Glycotechnology 2002, 76, 53-68.
5. Alexander, C.; Rietschel, E. T. Bacterial lipopolysaccharides and innate immunity. J. Endotoxin Res. 2001, 7, 167-202.
6. Suzuki, T. Role of NF-kB in Macrophage Activation. Endotoxin in Health and Disease; Marcel Dekker Inc.; New York, 1999; pp 509-520.
7. Tobias, P. S.; Soldau, K.; Ulevitch, R. J. Isolation of a lipopolysaccharide-binding acute phase reactant from rabbit serum. J. Exp. Med. 1986, 164, 777-793.
8. Wright, S. D.; Tobias, P. S.; Ulevitch, R. J.; Ramos, R. A. Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a novel receptor on macrophages. J. Exp. Med. 1989, 170, 1231-1241.
9. Kitchens, R. L.; Munford, R. S. CD14-dependent internalization of bacterial lipopolysaccharide (LPS) is strongly influenced by LPS aggregation but not by cellular responses to LPS. J. Immunol. 1998, 160, 1920-1928.
10. Haziot, A.; Chen, S.; Ferrero, E.; Low. M. G.; Silber, R.; Goyert, S. M. The monocyte differentiation antigen, CD14, is anchored to the cell membrane by a phosphatidylinositol linkage. J. Immunol. 1988, 141, 547-552.
11. Kitchens, R. L. Role of CD14 in cellular recognition of bacterial lipopolysaccharides. Chem. Immunol. 2000, 74, 61-82.
12. Medzhitov, R.; Preston-Hurlburt, P.; Janeway, C. A., Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997, 388, 394-397.
13. Poltorak, A.; He, X.; Smimova, I.; Liu, M. Y.; Huffel, C. V.; Du, X.; Birdwell, D.; Alejos, E.; Silva, M.; Galanos, C.; Freudenberg, M.; Ricciardi-Castagnoli, P.; Layton, B.; Beutler, B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998, 282, 2085-2088.
14. Chow, J. C.; Young, D. W.; Golenbock, D. T.; Christ, W. J.; Gusovsky, F. Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J. Biol. Chem. 1999, 274, 10689-10692.
15. Akashi, S.; Shimazu, R., Ogata, H.; Nagai, Y.; Takeda, K.; Kimoto, M.; Miyake, K. Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages. J. Immunol. 2000, 164, 3471-3475.
16. Shimazu, R.; Akashi, S.; Ogata, H.; Nagai, Y.; Fukudome, K.; Miyake, K.; Kimoto, M. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 1999, 189, 1777-1782.
17. Akashi, S.; Ogata, H.; Kirikae, F.; Kirikae, T.; Kawasaki, K.; Nishijima, M.; Shimazu, R.; Nagai, Y.; Fukudome, K.; Kimoto, M.; Miyake, K. Regulatory roles for CD14 and phosphatidylinositol in the signaling via toll-like receptor 4-MD-2. Biochem. Biophys. Res. Commun. 2000, 268, 172-177.
18. Yang, H.; Young, D. W.; Gusovsky, F.; Chow, J. C. Cellular events mediated by lipopolysaccharide-stimulated toll-like receptor 4. MD-2 is required for activation of mitogen-activated protein kinases and Elk-1. J. Biol. Chem. 2000, 275, 20861-20866.
19. Wurfel, M. M.; Kunitake, S. T.; Lichenstein, H.; Kane, J. P.; Wright, S. D. Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J. Exp. Med. 1994, 180, 1025-1035.
20. Wurfel, M. M.; Wright, S. D. Lipopolysaccharide (LPS) binding protein catalyzes binding of LPS to lipoproteins. Prog. Clin. Biol. Res. 1995, 392, 287-295.
21. Gordon, B. R.; Parker, T. S.; Levine, D. M.; Saal, S. D.; Wang, J. C.; Sloan, B. J.; Barie, P. S.; Rubin, A. L. Low lipid concentrations in critical illness: implications for preventing and treating endotoxemia. Crit. Care Med. 1996, 24, 584-589.
22. Westphal, O.; Luderitz, O. Chemische erforschung von lipopolysacchariden gram-negativer bakterien. Angew. Chemie. 1954, 66, 407-417.
23. Galanos, C.; Luderitz, O.; Rietschel, E. T.; Westphal, O.; Brade, H.; Brade, L.; Freudenberg, M.; Schade, U.; Imoto, M.; Yoshimura, H. Synthetic and natural Escherichia coli free lipid A express identical endotoxic activities. Eur. J. Biochem. 1985, 148, 1-5.
24. Young, L. S.; Gascon, R.; Alam, S.; Bermudez, L. E. Monoclonal antibodies for treatment of gram-negative infections. Rev. Infect. Dis. 1989, 11 Suppl. 7, S1564-1571.
25. Ziegler, E. J.; Fisher, C. J., Jr.; Sprung, C. L.; Straube, R. C.; Sadoff, J. C.; Foulke, G. E.; Wortel, C. H.; Fink, M. P.; Dellinger, R. P.; Teng, N. N.; Allen, I.E., Berger, H. J., Knatterud, G.L., LoBuglio, A.F., Smith, C.R., and the HA-1A Sepsis Study Group. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N. Engl. J. Med. 1991, 324, 429-436.
26. Bennett-Guerrero, E.; Ayuso, L.; Hamilton-Davies, C.; White, W. D.; Barclay, G. R.; Smith, P. K.; King, S. A.; Muhlbaier, L. H.; Newman, M. F.; Mythen, M. G. Relationship of preoperative antiendotoxin core antibodies and adverse outcomes following cardiac surgery. JAMA 1997, 277, 646-650.
27. Hamilton-Davies, C.; Barclay, G. R.; Cardigan, R. A.; McDonald, S. J.; Purdy, G.; Machin, S. J.; Webb, A. R. Relationship between preoperative endotoxin immune status, gut perfusion, and outcome from cardiac valve replacement surgery [see comments]. Chest 1997, 112, 1189-1196.
28. Freeman, B. D.; Natanson, C. Clinical Trials in Sepsis and Septic Shock in 1994 and 1995. Current Opinion in Critical Care 1995, 1, 349-357.
29. Brade, L.; Engel, R.; Christ, W. J.; Rietschel, E. T. A nonsubstituted primary hydroxyl group in position 6′ of free lipid A is required for binding of lipid A monoclonal antibodies. Infect. Immun. 1997, 65, 3961-3965.
30. Jones, L. H.; Altobell, I. L.; MacDonald, M. T.; Boyle, N. A.; Wentworth Jr, P.; Lerner, R. A.; Janda, K. D. Active Immunization with a Glycolipid Transition State Analogue Protects against Endotoxic Shock. Angew. Chem. Int. Ed. Engl. 2002, 41, 4241-4244.
31. Kenakian, T. P. Macromoleculat Targets for Drug Action. Comprehensive Medicinal Chemistry, The Rational Design, Mechanistic Study & Therapeutic Appication of Chemical Compounds; Pergamon Press: New York, 1990; pp 195-203.
32. Rietschel, E. T.; Kirikae, T.; Schade, F. U.; Mamat, U.; Schmidt, G.; Loppnow, H.; Ulmer, A. J.; Zahringer, U.; Seydel, U.; Di Padova, F.; Schreier, M. and Brade, H. Bacterial endotoxin: molecular relationships of structure to activity and function. FASEB J. 1994, 8, 217-225.
33. Wang, Y.; Hollingsworth, R. I. An NMR spectroscopy and molecular mechanics study of the molecular basis for the supramolecular structure of lipopolysaccharides. Biochemistry 1996, 35, 5647-5654.
34. Bulusu, M. A.; Waldstatten, P.; Hildebrandt, J.; Schutze, E.; Schulz, G. Acyclic analogues of lipid A: synthesis and biological activities. J. Med. Chem. 1992, 35, 3463-3469.
35. Tanamoto, K. Predominant role of the substituents on the hydroxyl groups of 3-hydroxy fatty acids of non-reducing glucosamine in lipid A for the endotoxic and antagonistic activity. FEBS Lett. 1994, 351, 325-329.
36. Brandenburg, K.; Seydel, U.; Schromm, A. B.; Loppnow, H.; Koch, M. H.; Rietschel, E. T. Conformation of lipid A, the endotoxic center of bacterial lipopolysaccharide. J. Endotoxin Research 1996, 3, 173-178.
37. Loppnow, H.; Libby, P.; Freudenberg, M.; Krauss, J. H.; Weckesser, J.; Mayer, H. Cytokine induction by lipopolysaccharide (LPS) corresponds to lethal toxicity and is inhibited by nontoxic Rhodobacter capsulatus LPS. Infect. Immun. 1990, 58, 3743-3750.
38. Takayama, K.; Qureshi, N.; Beutler, B.; Kirkland, T. N. Diphosphoryl lipid A from Rhodopseudomonas sphaeroides ATCC 17023 blocks induction of cachectin in macrophages by lipopolysaccharide. Infect. Immun. 1989, 57, 1336-1338.
39. Matsuura, M.; Kiso, M.; Hasegawa, A Activity of monosaccharide lipid A analogues in human monocytic cells as agonists or antagonists of bacterial lipopolysaccharide. Infect. Immun. 1999, 67, 6286-6292.
40. Ray, B. L.; Painter, G.; Raetz, C. R. The biosynthesis of gram-negative endotoxin. Formation of lipid A disaccharides from monosaccharide precursors in extracts of Escherichia coli. J. Biol. Chem. 1984, 259, 4852-4859.
41. Bulawa, C. E.; Raetz, C. R. The biosynthesis of gram-negative endotoxin. Identification and function of UDP-2,3-diacylglucosamine in Escherichia coli. J. Biol. Chem. 1984, 259, 4846-4851.
42. Danner, R. L.; Joiner, K. A.; Parrillo, J. E. Inhibition of endotoxin-induced priming of human neutrophils by lipid X and 3-Aza-lipid X. J. Clin. Invest. 1987, 80, 605-612.
43. Proctor, R. A.; Will, J. A.; Burhop, K. E.; Raetz, C. R. Protection of mice against lethal endotoxemia by a lipid A precursor. Infect Immun. 1986, 52, 905-907.
44. Golenbock, D. T.; Will, J. A.; Raetz, C. R.; Proctor, R. A. Lipid X ameliorates pulmonary hypertension and protects sheep from death due to endotoxin. Infect. Immun. 1987, 55, 2471-2476.
45. Danner, R. L.; Eichacker, P. Q.; Doerfler, M. E.; Hoffman, W. D.; Reilly, J. M.; Wilson, J.; MacVittie, T. J.; Stuetz, P.; Parrillo, J. E.; Natanson, C. Therapeutic trial of lipid X in a canine model of septic shock. J. Infect. Dis. 1993, 167, 378-384.
46. Danner, R. L.; Van Dervort, A. L.; Doerfler, M. E.; Stuetz, P.; Parrillo, J. E. Antiendotoxin activity of lipid A analogues: requirements of the chemical structure. Pharm. Res. 1990, 7, 260-263.
47. Aschauer, H.; Grob, A.; Hildebrandt, J.; Schuetze, E.; Stuetz, P. Highly purified lipid X is devoid of immunostimulatory activity. Isolation and characterization of immunostimulating contaminants in a batch of synthetic lipid X. J. Biol. Chem. 1990, 265, 9159-9164.
48. Lam, C.; Hildebrandt, J.; Schutze, E.; Rosenwirth, B.; Proctor, R. A.; Liehl, E.; Stutz, P. Immunostimulatory, but not antiendotoxin, activity of lipid X is due to small amounts of contaminating N,O-acylated disaccharide-1-phosphate: in vitro and in vivo reevaluation of the biological activity of synthetic lipid X. Infect. Immun. 1991, 59, 2351-2358.
49. Shiozaki, M.; Deguchi, N.; Macindoe, W. M.; Arai, M.; Miyazaki, H.; Mochizuki, T.; Tatsuta, T.; Ogawa, J.; Maeda, H.; Kurakata, S. Syntheses of 1-O-carboxyalkyl GLA-60 analogues. Carbohydr. Res. 1996, 283, 27-51.
50. Shiozaki, M.; Mochizuki, T.; Wakabayashi, T.; Kurakata, S.; Tatsuta, T.; Nishijima, M. Syntheisis of 2,6-anhydro-3-deoxy-5-O-[(R)-3-(tetradecanoylosy)tetradecanoyl] -D-glycero-D-ido-heptonic acid as a new potent endotoxin antagonist and its dimeric analogue. Tetrahedron Lett. 1996, 37.
51. Wollenweber, H. W.; Morrison, D. C. Synthesis and biochemical characterization of a photoactivatable, iodinatable, cleavable bacterial lipopolysaccharide derivative. J. Biol. Chem. 1985, 260, 15068-15074.
52. Wong, H. R.; Pitt, B. R.; Su, G. L.; Rossignol, D. P.; Steve, A. R.; Billiar, T. R.; Wang, S. C. Induction of lipopolysaccharide-binding protein gene expression in cultured rat pulmonary artery smooth muscle cells by interleukin 1 beta. Am. J. Respir. Cell Mol. Biol. 1995, 12, 449-454.
53. Qureshi, N.; Honovich, J. P.; Hara, H.; Cotter, R. J.; Takayama, K. Location of fatty acids in lipid A obtained from lipopolysaccharide of Rhodopseudomonas sphaeroides ATCC 17023. J. Biol. Chem. 1988, 263, 5502-5504.
54. Rose, J. R.; Christ, W. J.; Bristol, J. R.; Kawata, T.; Rossignol, D. P. Agonistic and antagonistic activities of bacterially derived Rhodobacter sphaeroides lipid A: Comparison with activities of synthetic material of the proposed structure and analogs. Infection and Immunity 1995, 63, 833-839.
55. Kusumoto, S.; Yoshimura, H.; Imoto, M.; Shimamoto, T.; Shiba, T. Chemical Synthesis of 1-Dephospho Derivative of Escherichia coli Lipid A. Tetrahedron Lett. 1985, 26.
56. Imoto, M.; Yoshimura, H.; Sakaguchi, N.; Kusumoto, S.; Shiba, T. Total Synthesis of Escherichia coli Lipid A. Tetrahedron Lett. 1985, 26, 1545-1548.
57. Shiozaki, M.; Kobayashi, Y.; Arai, M.; Ishida, N.; Hiraoka, T.; Nishijima, M.; Kuge, S.; Otsuka, T.; Akamatsu, Y. Synthesis of a 3-ether analogue of lipid A. Carbohydr. Res. 1991, 222, 69-82.
58. Christ, W. J.; Asano, O.; Robidoux, A. L. C.; Perez, M.; Wang, Y. A.; Dubuc, G. R.; Gavin, W. E.; Hawkins, L. D.; Mcguinness, P. D.; Mullarkey, M. A.; Lewis, M. D.; Kishi, Y., Kawata, T.; Bristol, J. R.; Rose, J. R.; Rossignol, D. P.; Kobayashi, S.; Hishinuma, L.; Kimura, A.; Asakawa, N.; Katayama, K.; Yamatsu, I. E5531, a pure endotoxin antagonist of high potency. Science 1995, 268, 80-83.
59. Kawata, T.; Bristol, J. R.; Rose, J. R.; Rossignol, D. P.; Christ, W. J.; Asano, O.; Dubuc, G. R.; Gavin, W. E.; Hawkins, L. D.; Kishi, Y.; McGuinness, P. D.; Mullarkey, M. A.; Perez, M.; Robidoux, A. L. C.; Yauan Wang, Kobayashi, S.; Kimura, A.; Katayama, K.; Yamatsu, I. Anti-endotoxin activity of a novel synthetic lipid A analog. Prog. Clin. Biol. Res. 1995, 392, 499-509.
60. Kawata, T.; Bristol, J. R.; Rossignol, D. P.; Rose, J. R.; Kobayashi, S.; Yokohama, H.; Ishibashi, A.; Christ, W. J.; Katayama, K.; Yamatsu, I.; Kishi, Y. E5531, a synthetic non-toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide. Br. J. Pharmacol. 1999, 127, 853-862.
61. Bunnell, E.; Lynn, M.; Habet, K.; Neumann, A.; Perdomo, C. A.; Friedhoff, L. T.; Rogers, S. L.; Parrillo, J. E. A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia. Crit. Care Med. 2000, 28, 2713-2720.
62. Perera, P. Y.; Manthey, C. L.; Stutz, P. L.; Hildebrandt, J.; Vogel, S. N. Induction of early gene expression in murine macrophages by synthetic lipid A analogs with differing endotoxic potentials. Infect. Immun. 1993, 61, 2015-2023.
63. Pedron, T.; Girard, R.; Eustache, J.; Bulusu, A. R.; Macher, I.; Radzyner-Vyplel, H.; Stutz, P. L.; Chaby, R. New synthetic analogs of lipid A as lipopolysaccharide agonists or antagonists of B lymphocyte activation. Int. Immunol. 1992, 4, 533-540.
64. Miyajima, K.; Achiwa, K. Lipid A and Related Compounds. XXXII. Synthesis of Biologically Active N-Acylated L-Homoserine-Containing D-Glucosamine-4-phosphate Derivatives Structurally Related to Lipid A. Chem. Pharm. Bull. 1997, 45.
65. Seydel, U.; Oikawa, M.; Fukase, K.; Kusumoto, S.; Brandenburg, K. Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity. Eur. J. Biochem. 2000, 267, 3032-3039.
66. Netea, M. G.; van Deuren, M.; Kullberg, B. J.; Cavaillon, J. M.; Van der Meer, J. W. Does the shape of lipid A determine the interaction of LPS with Toll-like receptors? Trends Immunol. 2002, 23, 135-139.
67. Krisovitch, S. M.; Regen, S. L. Nearest-neighbor recognition in phospholipid membranes: a molecular-level approach to the study of membrane suprastructure. J. Amer. Chem. Soc. 1992, 114, 9828-9835.
68. Seydel, U.; Hawkins, L.; Schromm, A. B.; Heine, H.; Scheel, O.; Koch, M. H. J.; Brandenburg, K. The generalized endotoxic priniciple. Eur. J. Immun. 2003, in press.
69. Ishikawa, Y.; Mukaida, N.; Kuno, K.; Rice, N.; Okamoto, S.; Matsushima, K. Establishment of lipopolysaccharide-dependent nuclear factor kappa B activation in a cell-free system. Journal of Biological Chemistry 1995, 270, 4158-4164.
70. Raetz, C. R. H. Biochemistry of Endotoxins. Ann. Rev. Biochem 1990, 59, 129-170.
71. Golenbock, D. T.; Hampton, R. Y.; Qureshi, N.; Takayama, K.; Raetz, C. R. Lipid A-like molecules that antagonize the effects of endotoxins on human monocytes. J. Biol. Chem. 1991, 266, 19490-19498.
72. Krauss, J. H.; Seydel, U.; Weckesser, J.; Mayer, H. Structural analysis of the nontoxic lipid A of Rhodobacter capsulatus 37b4. Eur. J. Biochem. 1989, 180, 519-526.
73. Kumazawa, E.; Soga, T.; Ono, Y.; Kumasawa, E.; Shioy, E.; Nakayama, K.; Uoto, K.; Osada, Y. Synthesis and biological activities of lipid A analogs: modification of a glycosidically bound group with chemically stable polar acidic groups and lipophilic groups on the disaccharide backbone with tetrdecanoly or N-dodecanoylglycyl groups. Chem. Pharm. Bull. (Tokyo) 1991, 39.
74. Sato, K.; Yung, Y. C.; Fukushima, A.; Saiki, I.; Takahashi, T. A.; Fujihara, M.; Tonooka, S.; Azuma, I. A novel synthetic lipid A analog with low endotoxicity, DT-5461, prevents lethal endotoxemia. Infection and Immunity 1995, 63, 2859-2866.
75. Watanabe, Y.; Mochizuki, T.; Shiozaki, M.; Kanai, S.; Kurakata, S.-I.; Nishijima, M. Synthesis of lipid A type pyran carboxylic acids with ether chains and their biological activities. Carbohydrate Res. 2001, 333.
76. Matsuura, M.; Shimada, S.; Kiso, M.; Hasegawa, A.; Nakano, M. Expression of endotoxic activities by synthetic monosaccharide lipid A analogs with alkyl-branched acyl substituents. Infect. Immun. 1995, 63, 1446-1451.
77. Salimath, P. V.; Weckesser, J.; Strittmatter, W.; Mayer, H. Structural studies on the non-toxic lipid A from Rhodopseudomonas sphaeroides ATCC 17023. Eur. J. Biochem. 1983, 136, 195-200.
78. Kaltashov, I. A.; Doroshenko, V.; Cotter, R. J.; Takayama, K.; Qureshi, N. Confirmation of the Structure of Lipid A Derived from the Lipopolysaccharide of Rhodobacter sphaeroides by a Combination of MALDI, LSIMS, and Tandem Mass Spectrometry. Anal. Chem. 1997, 69, 2317-2322.
79. Mullarkey, M.; Rose, J. R.; Bristol, J.; Kawata, T.; Kimura, A.; Kobayashi, S.; Przetak, M.; Chow, J.; Gusovsky, F.; Christ, W. J.; Rossignol, D. P. Inhibition of Endotoxin Response by E5564, a Novel Toll-Like Receptor 4-Directed Endotoxin Antagonist. J. Pharmacol. Exp. Ther. 2003, 304, 1093-1102.
80. Rose, J. R.; Mullarkey, M. A.; Christ, W. J.; Hawkins, L. D.; Lynn, M.; Kishi, Y.; Wasan, K. M.; Peteherych, K.; Rossignol, D. P. Consequences of interaction of a lipophilic endotoxin antagonist with plasma lipoproteins. Antimicrob. Agents Chemother. 2000, 44, 504-510.
81. Wasan, K. M.; Strobel, F. W.; Parrott, S. C.; Lynn, M.; Christ, W. J.; Hawkins, L. D.; Rossignol, D. P. Lipoprotein distribution of a novel endotoxin antagonist, E5531, in plasma from human subjects with various lipid levels. Antimicrob. Agents Chemother. 1999, 43, 2562-2564.
82. Beutler, B.; Milsark, I. W.; Cerami, A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985, 229, 869-871.
83. Kitchens, R. L.; Munford, R. S. Enzymatically deacylated lipopolysaccharide (LPS) can antagonize LPS at multiple sites in the LPS recognition pathway. Journal of Biological Chemistry 1995, 270, 9904-9910.
84. Ulmer, A. J.; Heine, H.; Feist, W.; Kusumoto, S.; Kusama, T.; Brade, H.; Schade, U. Biological Activity Of Synthetic Phosphonooxyethyl Analogs Of Lipid a. Infection and Immunity, 1992, 60, 3309-3314.
85. Rossignol, D. P.; Christ, W. J.; Hawkins, L. D.; Kobayashi, S.; Kawata, T.; Lynn, M.; Yamatsu, I.; Kishi, Y. Synthetic Endotoxin Antagonists. Endotoxin in Health and Disease; Marcel Dekker Inc.; New York, 1999; pp 699-717.
86. Lorsbach, R. B.; Murphy, W. J.; Lowenstein, C. J.; Snyder, S. H.; Russell, S. W. Expression of the nitric oxide synthase gene in mouse macrophages activated for tumor cell killing. Molecular basis for the synergy between interferon-gamma and lipopolysaccharide. J. Biol. Chem. 1993, 268, 1908-1913.
87. Suganuma, A.; Rossignol, D. P.; Kaneko, K.; LaRochelle, A. W.; Kerns, W. D. Clinical pharmacology of E5564, a lipid A antagonist, in a canine lipopolysaccharide challenge model. J. Endotoxin Res. 2000, 6, 115.
88. Morrison, D. C.; Bucklin, S. E. Evidence for antibiotic-mediated endotoxin release as a contributing factor to lethality in experimental gram-negative sepsis. Scand. J. Infect. Dis. Suppl. 1996, 101, 3-8.
89. Wasan, K. M.; Sivak, O.; Cote, R. A.; MacInnes, A. I.; Boulanger, K. D.; Lynn, M.; Christ, W. J.; Hawkins, L. D.; Rossignol, D. P. Association of the endotoxin antagonist E5564 with high-density lipoproteins in vitro: dependence on low-density and triglyceriderich lipoprotein concentrations. Antimicrob. Agents Chemother. 2003, 47, 2796-2803.
90. Opal, S. M.; Scannon, P. J.; Vincent, J. L.; White, M.; Carroll, S. F.; Palardy, J. E.; Parejo, N. A.; Pribble, J. P.; Lemke, J. H. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. J. Infect. Dis. 1999, 180, 1584-1589.
91. Parker, T. S.; Levine, D. M.; Chang, J. C. C.; Laxer, J.; Coffin, C. C.; Rubin, A. L. Reconstituted high-density lipoprotein neutralizes gram-negative bacterial lipopolysaccharides in human whole blood. Infection and Immunity 1995, 63, 253-258.
92. Pajkrt, D.; Doran, J. E.; Koster, F.; Lerch, P. G.; Arnet, B.; van der Poll, T.; ten Cate, J. W.; van Deventer, S. J. Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia. J. Exp. Med. 1996, 184, 1601-1608.
93. Hochstein, H. D.; Fitzgerald, E. A.; McMahon, F. G.; Vargas, R. Properties of US standard endotoxin (EC-5) in human male volunteers. J. Endotoxin Res. 1994, 1, 52-56.
94. Parrillo, J. E.; Parker, M. M.; Natanson, C.; Suffredini, A. F.; Danner, R. L.; Cunnion, R. E.; Ognibene, F. P. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy [see comments]. Ann. Intern. Med. 1990, 113, 227-242.
95. Suffredini, A. F.; Harpel, P. C.; Parrillo, J. E. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N. Engl. J. Med. 1989, 320, 1165-1172.
96. Lynn, M.; Wong, Y. N.; Wheeler, J. L.; Kao, R. J.; Perdomo, C. A.; Noveck, R.; Vargas, R.; D'Angelo, T.; Gotzkowsky, S.; McMahon, F. G.; Wasan, K. M.; Rossignol, D. P. Extended in vivo pharmacodynamic activity of E5564 in normal volunteers with experimental endotoxemia [corrected]. J. Pharmacol. Exp. Ther. 2004, 308, 175-181.
97. Bernard, G. R.; Vincent, J. L.; Laterre, P. F.; LaRosa, S. P.; Dhainaut, J. F.; Lopez-Rodriguez, A.; Steingrub, J. S.; Garber, G. E.; Helterbrand, J. D.; Ely, E. W.; Fisher, C. J., Jr. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 2001, 344, 699-709.
98. Wong, Y. N.; Rossignol, D.; Rose, J. R.; Kao, R.; Carter, A.; Lynn, M. Safety, Pharmacokinetics and Pharmacodynamics of E5564, A Lipid A Antagonist, During an Ascending Single-Dose Clinical Study. Journal of Clinical Pharmacology 2003, 43, 735-742.
99. Rossignol, D. P.; Lynn, M. Antagonism of in vivo and ex vivo response to endotoxin by E5564, a novel synthetic lipid A antagonist. J. Endotoxin Research 2002, 8, 483-488.
100. Rossignol, D. P.; Wasan, K. M.; Choo, E.; Yau, E.; Wong, N.; Rose, J.; Moran, J.; Lynn, M. Analysis of the Safety, Pharmacokinetics, Pharmacodynamics and Plasma Lipoprotein Distribution of Eritoran (E5564) during Continuous Intravenous Infusion into Healthy Volunteers. Antimicrob. Agents Chemother. 2004, in press.