An overview of investigational toxin-directed therapies for the adjunctive management of Bacillus anthracis infection and sepsis

Expert Opinion on Investigational Drugs

Volumn 24, Issue 7, 2015, Pages 851-865

  Ohanjanian, Lernik ^a   Remy, Kenneth E ^a   Li, Yan ^a   Cui, Xizhong ^a   Eichacker, Peter Q ^a  

^a NATIONAL INSTITUTES OF HEALTH   (United States)

Author keywords

Anthrax; Bacillus anthracis; Lethal and edema toxins; Toxin directed agents; Treatment

Indexed keywords

ANTHRAX TOXIN; ANTIGEN; CELL ENZYME; CMG2 PROTEIN; EDEMA TOXIN; FURIN; LETHAL TOXIN; OLIGOMER; PROTECTIVE ANTIGEN; PROTEIN; TEM8 PROTEIN; UNCLASSIFIED DRUG; BACTERIAL ANTIGEN; BACTERIAL TOXIN;

ANTHRAX; ANTIGEN BINDING; CARDIOVASCULAR EFFECT; CHANNEL GATING; EDEMA FACTOR; ENDOSOME; ENZYME ACTIVITY; GENE; GENE TRANSLOCATION; HUMAN; LETHAL GENE; NONHUMAN; OLIGOMERIZATION; REVIEW; SEPSIS; SHOCK; TOXIN STRUCTURE; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; METABOLISM;

ANIMALS; ANTHRAX; ANTIGENS, BACTERIAL; BACTERIAL TOXINS; HUMANS; MOLECULAR STRUCTURE; SEPSIS;

EID: 84934965566     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2015.1041587     Document Type: Review

References (150)

1. Remy KE, Qiu P, Li Y, et al. B. anthracis associated cardiovascular dysfunction and shock: the potential contribution of both non-toxin and toxin components. BMC Med 2013;11:217
2. Sweeney DA, Hicks CW, Cui X, et al. Anthrax infection. Am J Respir Crit Care Med 2011;184(12):1333-41
3. Hicks CW, Sweeney DA, Cui X, et al. An overview of anthrax infection including the recently identified form of disease in injection drug users. Intensive Care Med 2012;38(7):1092-104
4. Booth M, Donaldson L, Cui X, et al. Confirmed Bacillus anthracis infection among persons who inject drugs, Scotland, 2009-2010. Emerg Infect Dis 2014;20(9):1452-63
5. Jernigan JA, Stephens DS, Ashford DA, et al. Bioterrorism-related inhalational anthrax: the first 10 cases reported in the United States. Emerg Infect Dis 2001;7(6):933-44
6. Walsh JJ, Pesik N, Quinn CP, et al. A case of naturally acquired inhalation anthrax: clinical care and analyses of antiprotective antigen immunoglobulin G and lethal factor. Clin Infect Dis 2007;44(7):968-71
7. Anaraki S, Addiman S, Nixon G, et al. Investigations and control measures following a case of inhalation anthrax in East London in a drum maker and drummer, October 2008. Euro Surveill 2008;13(51):pii: 19076
8. Klempner MS, Talbot EA, Lee SI, et al. Case records of the Massachusetts General Hospital. Case 25-2010. A 24-year-old woman with abdominal pain and shock. N Engl J Med 2010;363(8):766-77
9. Berger T, Kassirer M, Aran AA. Injectional anthrax-new presentation of an old disease. Euro Surveill 2014;19(32):pii: 20877
10. Sprenkle MD, Griffith J, Marinelli W, et al. Lethal factor and anti-protective antigen IgG levels associated with inhalation anthrax, Minnesota, USA. Emerg Infect Dis 2014;20(2):310-14
11. Sherer K, Li Y, Cui X, Eichacker PQ. Lethal and edema toxins in the pathogenesis of Bacillus anthracis septic shock: implications for therapy. Am J Respir Crit Care Med 2007;175(3):211-21
12. Stevenson EK, Rubenstein AR, Radin GT, et al. Two decades of mortality trends among patients with severe sepsis: a comparative meta-analysis. Crit Care Med 2014;42(3):625-31
13. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013;369(21):2063
14. Goldman DL, Casadevall A. Anthrax-associated shock. Front Biosci 2008;13:4009-14
15. Golden HB, Watson LE, Lal H, et al. Anthrax toxin: pathologic effects on the cardiovascular system. Front Biosci 2009;14:2335-57
16. Hicks CW, Cui X, Sweeney DA, et al. The potential contributions of lethal and edema toxins to the pathogenesis of anthrax associated shock. Toxins 2011;3(9):1185-202
17. Liu S, Moayeri M, Leppla SH. Anthrax lethal and edema toxins in anthrax pathogenesis. Trends Microbiol 2014;22(6):317-25
18. Young JA, Collier RJ. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu Rev Biochem 2007;76:243-65
19. Bromberg-White J, Lee CS, Duesbery N. Consequences and utility of the zincdependent metalloprotease activity of anthrax lethal toxin. Toxins 2010;2(5):1038-53
20. Moayeri M, Sastalla I, Leppla SH. Anthrax and the inflammasome. Microbes Infect 2012;14(5):392-400
21. Tang WJ, Guo Q. The adenylyl cyclase activity of anthrax edema factor. Mol Aspects Med 2009;30(6):423-30
22. Hicks CW, Li Y, Okugawa S, et al. Anthrax edema toxin has cAMPmediated stimulatory effects and highdose lethal toxin has depressant effects in an isolated perfused rat heart model. Am J Physiol Heart Circ Physiol 2011;300(3):H1108-18
23. Sayner SL. Emerging themes of cAMP regulation of the pulmonary endothelial barrier. Am J Physiol Lung Cell Mol Physiol 2011;300(5):L667-78
24. Guichard A, Nizet V, Bier E. New insights into the biological effects of anthrax toxins: linking cellular to organismal responses. Microbes Infect 2012;14(2):97-118
25. Li Y, Cui X, Solomon SB, et al. B. anthracis edema toxin increases cAMP levels and inhibits phenylephrinestimulated contraction in a rat aortic ring model. Am J Physiol Heart Circ Physiol 2013;305(2):H238-50
26. Nestorovich EM, Bezrukov SM. Designing inhibitors of anthrax toxin. Expert Opin Drug Discov 2014;9(3):299-318
27. Bouzianas DG. Current and future medical approaches to combat the anthrax threat. J Med Chem 2010;53(11):4305-31
28. Van Der Goot G, Young JA. Receptors of anthrax toxin and cell entry. Mol Aspects Med 2009;30(6):406-12
29. Martchenko M, Jeong SY, Cohen SN. Heterodimeric integrin complexes containing beta1-integrin promote internalization and lethality of anthrax toxin. Proc Natl Acad Sci USA 2010;107(35):15583-8
30. Artenstein AW, Opal SM. Novel approaches to the treatment of systemic anthrax. Clin Infect Dis 2012;54(8):1148-61
31. Thoren KL, Krantz BA. The unfolding story of anthrax toxin translocation. Mol Microbiol 2011;80(3):588-95
32. Collier RJ. Membrane translocation by anthrax toxin. Mol Aspects Med 2009;30(6):413-22
33. Bann JG. Anthrax toxin protective antigen-insights into molecular switching from prepore to pore. Protein Sci 2012;21(1):1-12
34. Kumar BVS, Malik S, Grandhi P, et al. Anthrax lethal factor inhibitors as potential countermeasure of the infection. Curr Top Med Chem 2014;14(17):1977-89
35. Coate EA, Kocsis AG, Peters KN, et al. Remote monitoring of the progression of primary pneumonic plague in Brown Norway rats in high-capacity, highcontainment housing. Pathog Dis 2014;71(2):265-75
36. Kammanadiminti S, Patnaikuni RK, Comer J, et al. Combination therapy with antibiotics and anthrax immune globulin intravenous (AIGIV) is potentially more effective than antibiotics alone in rabbit model of inhalational anthrax. PLoS One 2014;9(9):e106393
37. Mytle N, Hopkins RJ, Malkevich NV, et al. Evaluation of intravenous anthrax immune globulin for treatment of inhalation anthrax. Antimicrob Agents Chemother 2013;57(11):5684-92
38. Hendricks KA, Wright ME, Shadomy SV, et al. Centers for disease control and prevention expert panel meetings on prevention and treatment of anthrax in adults. Emerg Infect Dis 2014;20(2):doi: 10.3201/eid2002.130687
39. Migone TS, Subramanian GM, Zhong J, et al. Raxibacumab for the treatment of inhalational anthrax. N Engl J Med 2009;361(2):135-44
40. Corey A, Migone TS, Bolmer S, et al. Bacillus anthracis protective antigen kinetics in inhalation spore-challenged untreated or levofloxacin/raxibacumabtreated New Zealand white rabbits. Toxins 2013;5(1):120-38
41. Migone TS, Bolmer S, Zhong J, et al. Added benefit of raxibacumab to antibiotic treatment of inhalational anthrax. Antimicrob Agents Chemother 2015;59(2):1145-51
42. Barochia AV, Cui X, Sun J, et al. Protective antigen antibody augments hemodynamic support in anthrax lethal toxin shock in canines. J Infect Dis 2012;205(5):818-29
43. Mohamed N, Clagett M, Li J, et al. A high-affinity monoclonal antibody to anthrax protective antigen passively protects rabbits before and after aerosolized Bacillus anthracis spore challenge. Infect Immun 2005;73(2):795-802
44. Biron B, Beck K, Dyer D, et al. Efficacy of ETI-204 monoclonal antibody as an adjunct therapy in a New Zealand white rabbit partial survival model for inhalational anthrax. Antimicrob Agents Chemother 2015;59(4):2206-14
45. Anthium-Investigational Aanthrax anti-toxin therapeutics. Available from: www.elusys.com [Last accessed 02 November 2015]
46. Albrecht MT, Li H, Williamson ED, et al. Human monoclonal antibodies against anthrax lethal factor and protective antigen act independently to protect against Bacillus anthracis infection and enhance endogenous immunity to anthrax. Infect Immun 2007;75(11):5425-33
47. Chen Z, Moayeri M, Zhou YH, et al. Efficient neutralization of anthrax toxin by chimpanzee monoclonal antibodies against protective antigen. J Infect Dis 2006;193(5):625-33
48. Altaweel L, Chen Z, Moayeri M, et al. Delayed treatment with W1-mAb, a chimpanzee-derived monoclonal antibody against protective antigen, reduces mortality from challenges with anthrax edema or lethal toxin in rats and with anthrax spores in mice. Crit Care Med 2011;39(6):1439-47
49. Hao L, Zheng F, Xiong S, et al. Preparation and evaluation of humanmurine chimeric antibody against protective antigen of Bacillus anthracis. Int J Mol Sci 2014;15(10):18496-507
50. Scobie HM, Young JA. Interactions between anthrax toxin receptors and protective antigen. Curr Opin Microbiol 2005;8(1):106-12
51. Sharma S, Thomas D, Marlett J, et al. Efficient neutralization of antibodyresistant forms of anthrax toxin by a soluble receptor decoy inhibitor. Antimicrob Agents Chemother 2009;53(3):1210-12
52. Cai C, Che J, Xu L, et al. Tumor endothelium marker-8 based decoys exhibit superiority over capillary morphogenesis protein-2 based decoys as anthrax toxin inhibitors. PLoS One 2011;6(6):e20646
53. Wycoff KL, Belle A, Deppe D, et al. Recombinant anthrax toxin receptor-Fc fusion proteins produced in plants protect rabbits against inhalational anthrax. Antimicrob Agents Chemother 2011;55(1):132-9
54. Vuyisich M, Gnanakaran S, Lovchik JA, et al. A dual-purpose protein ligand for effective therapy and sensitive diagnosis of anthrax. Protein J 2008;27(5):292-302
55. Thomas D, Naughton J, Cote C, et al. Delayed toxicity associated with soluble anthrax toxin receptor decoy-Ig fusion protein treatment. PLoS One 2012;7(4):e34611
56. Basha S, Rai P, Poon V, et al. Polyvalent inhibitors of anthrax toxin that target host receptors. Proc Natl Acad Sci USA 2006;103(36):13509-13
57. Rogers MS, Cryan LM, Habeshian KA, et al. A FRET-based high throughput screening assay to identify inhibitors of anthrax protective antigen binding to capillary morphogenesis gene 2 protein. PLoS One 2012;7(6):e39911
58. Cryan LM, Habeshian KA, Caldwell TP, et al. Identification of small molecules that inhibit the interaction of TEM8 with anthrax protective antigen using a FRET assay. J Biomol Screen 2013;18(6):714-25
59. Moayeri M, Wiggins JF, Lindeman RE, Leppla SH. Cisplatin inhibition of anthrax lethal toxin. Antimicrob Agents Chemother 2006;50(8):2658-65
60. Arevalo MT, Navarro A, Arico CD, et al. Targeted silencing of anthrax toxin receptors protects against anthrax toxins. J Biol Chem 2014;289(22):15730-8
61. Smith K, Crowe SR, Garman L, et al. Human monoclonal antibodies generated following vaccination with AVA provide neutralization by blocking furin cleavage but not by preventing oligomerization. Vaccine 2012;30(28):4276-83
62. Crowe SR, Ash LL, Engler RJ, et al. Select human anthrax protective antigen epitope-specific antibodies provide protection from lethal toxin challenge. J Infect Dis 2010;202(2):251-60
63. Sarac MS, Peinado JR, Leppla SH, Lindberg I. Protection against anthrax toxemia by hexa-D-arginine in vitro and in vivo. Infect Immun 2004;72(1):602-5
64. Kacprzak MM, Peinado JR, Than ME, et al. Inhibition of furin by polyargininecontaining peptides: nanomolar inhibition by nona-D-arginine. J Biol Chem 2004;279(35):36788-94
65. Peinado JR, Kacprzak MM, Leppla SH, Lindberg I. Cross-inhibition between furin and lethal factor inhibitors. Biochem Biophys Res Commun 2004;321(3):601-5
66. Shiryaev SA, Remacle AG, Ratnikov BI, et al. Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens. J Biol Chem 2007;282(29):20847-53
67. Remacle AG, Gawlik K, Golubkov VS, et al. Selective and potent furin inhibitors protect cells from anthrax without significant toxicity. Int J Biochem Cell Biol 2010;42(6):987-95
68. Opal SM, Artenstein AW, Cristofaro PA, et al. Inter-alpha-inhibitor proteins are endogenous furin inhibitors and provide protection against experimental anthrax intoxication. Infect Immun 2005;73(8):5101-5
69. Opal SM, Lim YP, Cristofaro P, et al. Inter-alpha inhibitor proteins: a novel therapeutic strategy for experimental anthrax infection. Shock 2011;35(1):42-4
70. Komiyama T, Swanson JA, Fuller RS. Protection from anthrax toxin-mediated killing of macrophages by the combined effects of furin inhibitors and chloroquine. Antimicrob Agents Chemother 2005;49(9):3875-82
71. Wein AN, Williams BN, Liu S, et al. Small molecule inhibitors of Bacillus anthracis protective antigen proteolytic activation and oligomerization. J Med Chem 2012;55(18):7998-8006
72. Sawada-Hirai R, Jiang I, Wang F, et al. Human anti-anthrax protective antigen neutralizing monoclonal antibodies derived from donors vaccinated with anthrax vaccine adsorbed. J Immune Based Ther Vaccines 2004;2(1):5
73. Wang F, Ruther P, Jiang I, et al. Human monoclonal antibodies that neutralize anthrax toxin by inhibiting heptamer assembly. Hum Antibodies 2004;13(4):105-10
74. Peterson JW, Comer JE, Baze WB, et al. Human monoclonal antibody AVP-21D9 to protective antigen reduces dissemination of the Bacillus anthracis Ames strain from the lungs in a rabbit model. Infect Immun 2007;75(7):3414-24
75. Peterson JW, Comer JE, Noffsinger DM, et al. Human monoclonal anti-protective antigen antibody completely protects rabbits and is synergistic with ciprofloxacin in protecting mice and guinea pigs against inhalation anthrax. Infect Immun 2006;74(2):1016-24
76. Malkevich NV, Basu S, Rudge TL, et al. Effect of anthrax immune globulin on response to BioThrax (anthrax vaccine adsorbed) in New Zealand white rabbits. Antimicrob Agents Chemother 2013;57(11):5693-6
77. Vitale L, Blanset D, Lowy I, et al. Prophylaxis and therapy of inhalational anthrax by a novel monoclonal antibody to protective antigen that mimics vaccine-induced immunity. Infect Immun 2006;74(10):5840-7
78. Riddle V, Leese P, Blanset D, et al. Phase I study evaluating the safety and pharmacokinetics of MDX-1303, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers. Clin Vaccine Immunol 2011;18(12):2136-42
79. Froude JW II, Thullier P, Pelat T. Antibodies against anthrax: mechanisms of action and clinical applications. Toxins 2011;3(11):1433-52
80. Rubert Perez C, López-Perez D, Chmielewski J, Lipton M. Small molecule inhibitors of anthrax toxin-induced cytotoxicity targeted against protective antigen. Chem Biol Drug Des 2012;79(3):260-9
81. Steiniger SC, Altobell LJ III, Zhou B, Janda KD. Selection of human antibodies against cell surface-associated oligomeric anthrax protective antigen. Mol Immunol 2007;44(10):2749-55
82. Zhou B, Carney C, Janda KD. Selection and characterization of human antibodies neutralizing Bacillus anthracis toxin. Bioorg Med Chem 2008;16(4):1903-13
83. Mourez M, Kane RS, Mogridge J, et al. Designing a polyvalent inhibitor of anthrax toxin. Nat Biotechnol 2001;19(10):958-61
84. Gujraty K, Sadacharan S, Frost M, et al. Functional characterization of peptidebased anthrax toxin inhibitors. Mol Pharm 2005;2(5):367-72
85. Gujraty KV, Joshi A, Saraph A, et al. Synthesis of polyvalent inhibitors of controlled molecular weight: structureactivity relationship for inhibitors of anthrax toxin. Biomacromolecules 2006;7(7):2082-5
86. Rai PR, Saraph A, Ashton R, et al. Raftlike polyvalent inhibitors of the anthrax toxin: modulating inhibitory potency by formation of lipid microdomains. Angew Chem 2007;46(13):2207-9
87. Gujraty KV, Yanjarappa MJ, Saraph A, et al. Synthesis of homopolymers and copolymers containing an active ester of acrylic acid by RAFT: scaffolds for controlling polyvalent ligand display. J Polym Sci A Polym Chem 2008;46(21):7246-57
88. Joshi A, Kate S, Poon V, et al. Structure-based design of a heptavalent anthrax toxin inhibitor. Biomacromolecules 2011;12(3):791-6
89. Little SF, Leppla SH, Friedlander AM. Production and characterization of monoclonal antibodies against the lethal factor component of Bacillus anthracis lethal toxin. Infect Immun 1990;58(6):1606-13
90. Zhao P, Liang X, Kalbfleisch J, et al. Neutralizing monoclonal antibody against anthrax lethal factor inhibits intoxication in a mouse model. Hum Antibodies 2003;12(4):129-35
91. Nguyen ML, Terzyan S, Ballard JD, et al. The major neutralizing antibody responses to recombinant anthrax lethal and edema factors are directed to non-cross-reactive epitopes. Infect Immun 2009;77(11):4714-23
92. Lim NK, Kim JH, Oh MS, et al. An anthrax lethal factor-neutralizing monoclonal antibody protects rats before and after challenge with anthrax toxin. Infect Immun 2005;73(10):6547-51
93. Pelat T, Hust M, Laffly E, et al. Highaffinity, human antibody-like antibody fragment (single-chain variable fragment) neutralizing the lethal factor (LF) of Bacillus anthracis by inhibiting protective antigen-LF complex formation. Antimicrob Agents Chemother 2007;51(8):2758-64
94. Vor dem Esche U, Huber M, Zgaga-Griesz A, et al. Passive vaccination with a human monoclonal antibody: Generation of antibodies and studies for efficacy in Bacillus anthracis infections. Immunobiology 2011;216(7):847-53
95. Ding G, Chen X, Zhu J, et al. A human/murine chimeric fab antibody neutralizes anthrax lethal toxin in vitro. Clin Dev immunol 2013;2013:475809
96. Stienstra S. The use of anthrax and orthopox therapeutic antibodies from human origin in biodefense. J Bioterr Biodef 2012.3:3. Available from: http://dx.doi. org/10.4172/2157-2526.S1.006 [Last accessed 02 October 2015]
97. Little SF, Leppla SH, Burnett JW, Friedlander AM. Structure-function analysis of Bacillus anthracis edema factor by using monoclonal antibodies. Biochem Biophys Res Commun 1994;199(2):676-82
98. Kulshreshtha P, Bhatnagar R. Inhibition of anthrax toxins with a bispecific monoclonal antibody that cross reacts with edema factor as well as lethal factor of Bacillus anthracis. Mol Immunol 2011;48(15-16):1958-65
99. Leysath CE, Chen KH, Moayeri M, et al. Mouse monoclonal antibodies to anthrax edema factor protect against infection. Infect Immun 2011;79(11):4609-16
100. Rosenfeld R, Marcus H, Ben-Arie E, et al. Isolation and chimerization of a highly neutralizing antibody conferring passive protection against lethal Bacillus anthracis infection. PLoS One 2009;4(7):e6351
101. Mechaly A, Levy H, Epstein E, et al. A novel mechanism for antibody-based anthrax toxin neutralization: inhibition of prepore-to-pore conversion. J Biol Chem 2012;287(39):32665-73
102. Sellman BR, Mourez M, Collier RJ. Dominant-negative mutants of a toxin subunit: an approach to therapy of anthrax. Science 2001;292(5517):695-7
103. Singh Y, Khanna H, Chopra AP, Mehra V. A dominant negative mutant of Bacillus anthracis protective antigen inhibits anthrax toxin action in vivo. J Biol Chem 2001;276(25):22090-4
104. Cao S, Guo A, Liu Z, et al. Investigation of new dominant-negative inhibitors of anthrax protective antigen mutants for use in therapy and vaccination. Infect Immun 2009;77(10):4679-87
105. Wu G, Feng C, Cao S, et al. Identification of new dominant-negative mutants of anthrax protective antigen using directed evolution. Appl Biochem Biotechnol 2012;168(5):1302-10
106. Friedlander AM. Macrophages are sensitive to anthrax lethal toxin through an acid-dependent process. J Biol Chem 1986;261(16):7123-6
107. Artenstein AW, Opal SM, Cristofaro P, et al. Chloroquine enhances survival in Bacillus anthracis intoxication. J Infect Dis 2004;190(9):1655-60
108. Hirsh MI, Cohen V. Chloroquine prevents T lymphocyte suppression induced by anthrax lethal toxin. J Infect Dis 2006;194(7):1003-7
109. Hirsh MI, Manov I, Cohen-Kaplan V, Iancu TC. Ultrastructural features of lymphocyte suppression induced by anthrax lethal toxin and treated with chloroquine. Lab Invest 2007;87(2):182-8
110. Orlik F, Schiffler B, Benz R. Anthrax toxin protective antigen: inhibition of channel function by chloroquine and related compounds and study of binding kinetics using the current noise analysis. Biophys J 2005;88(3):1715-24
111. Beitzinger C, Bronnhuber A, Duscha K, et al. Designed azolopyridinium salts block protective antigen pores in vitro and protect cells from anthrax toxin. PLoS One 2013;8(6):e66099
112. Sanchez AM, Thomas D, Gillespie EJ, et al. Amiodarone and bepridil inhibit anthrax toxin entry into host cells. Antimicrob Agents Chemother 2007;51(7):2403-11
113. Zhu PJ, Hobson JP, Southall N, et al. Quantitative high-throughput screening identifies inhibitors of anthrax-induced cell death. Bioorg Med Chem 2009;17(14):5139-45
114. Karginov VA. Cyclodextrin derivatives as anti-infectives. Curr Opin Pharmacol 2013;13(5):717-25
115. Karginov VA, Yohannes A, Robinson TM, et al. b-Cyclodextrin derivatives that inhibit anthrax lethal toxin. Bioorg Med Chem 2006;14(1):33-40
116. Backer MV, Patel V, Jehning BT, et al. Inhibition of anthrax protective antigen outside and inside the cell. Antimicrob Agents Chemother 2007;51(1):245-51
117. Karginov VA, Nestorovich EM, Moayeri M, et al. Blocking anthrax lethal toxin at the protective antigen channel by using structure-inspired drug design. Proc Natl Acad Sci USA 2005;102(42):15075-80
118. Karginov VA, Nestorovich EM, Yohannes A, et al. Search for cyclodextrin-based inhibitors of anthrax toxins: synthesis, structural features, and relative activities. Antimicrob Agents Chemother 2006;50(11):3740-53
119. Moayeri M, Robinson TM, Leppla SH, Karginov VA. In vivo efficacy of betacyclodextrin derivatives against anthrax lethal toxin. Antimicrob Agents Chemother 2008;52(6):2239-41
120. Kong Y, Guo Q, Yu C, et al. Fusion protein of Delta 27LFn and EFn has the potential as a novel anthrax toxin inhibitor. FEBS Lett 2009;583(8):1257-6
121. Dalkas GA, Papakyriakou A, Vlamis-Gardikas A, Spyroulias GA. Low molecular weight inhibitors of the protease anthrax lethal factor. Mini Rev Med Chem 2008;8(3):290-306
122. Turk BE. Discovery and development of anthrax lethal factor metalloproteinase inhibitors. Curr Pharm Biotechnol 2008;9(1):24-33
123. Tonello F, Montecucco C. The anthrax lethal factor and its MAPK kinasespecific metalloprotease activity. Mol Aspects Med 2009;30(6):431-8
124. Tonello F, Seveso M, Marin O, et al. Screening inhibitors of anthrax lethal factor. Nature 2002;418(6896):386
125. Turk BE, Wong TY, Schwarzenbacher R, et al. The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor. Nat Struct Mol Biol 2004;11(1):60-6
126. Xiong Y, Wiltsie J, Woods A, et al. The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection. Bioorg Med Chem Lett 2006;16(4):964-8
127. Shoop WL, Xiong Y, Wiltsie J, et al. Anthrax lethal factor inhibition. Proc Natl Acad Sci USA 2005;102(22):7958-63
128. Jiao GS, Kim S, Moayeri M, et al. Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain. Bioorg Med Chem Lett 2012;22(6):2242-6
129. Kim S, Jiao GS, Moayeri M, et al. Antidotes to anthrax lethal factor intoxication. Part 2: structural modifications leading to improved in vivo efficacy. Bioorg Med Chem Lett 2011;21(7):2030-3
130. Jiao GS, Kim S, Moayeri M, et al. Antidotes to anthrax lethal factor intoxication. Part 1: Discovery of potent lethal factor inhibitors with in vivo efficacy. Bioorg Med Chem Lett 2010;20(22):6850-3
131. Moayeri M, Crown D, Jiao GS, et al. Small-molecule inhibitors of lethal factor protease activity protect against anthrax infection. Antimicrob Agents Chemother 2013;57(9):4139-45
132. Forino M, Johnson S, Wong TY, et al. Efficient synthetic inhibitors of anthrax lethal factor. Proc Natl Acad Sci USA 2005;102(27):9499-504
133. Kim C, Gajendran N, Mittrucker HW, et al. Human alpha-defensins neutralize anthrax lethal toxin and protect against its fatal consequences. Proc Natl Acad Sci USA 2005;102(13):4830-5
134. Dell'Aica I, Dona M, Tonello F, et al. Potent inhibitors of anthrax lethal factor from green tea. EMBO Rep 2004;5(4):418-22
135. Wickliffe KE, Leppla SH, Moayeri M. Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome. Cell Microbiol 2008;10(2):332-43
136. Chen Z, Moayeri M, Zhao H, et al. Potent neutralization of anthrax edema toxin by a humanized monoclonal antibody that competes with calmodulin for edema factor binding. Proc Natl Acad Sci USA 2009;106(32):13487-92
137. Winterroth L, Rivera J, Nakouzi AS, et al. Neutralizing monoclonal antibody to edema toxin and its effect on murine anthrax. Infect Immun 2010;78(6):2890-8
138. Seifert R, Dove S. Inhibitors of Bacillus anthracis edema factor. Pharmacol Ther 2013;140(2):200-12
139. Shen Y, Zhukovskaya NL, Zimmer MI, et al. Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection. Proc Natl Acad Sci USA 2004;101(9):3242-7
140. Tang WJ, Guo Q. The adenylyl cyclase activity of anthrax edema factor. Mol Aspects Med 2009;30(6):423-30
141. Lee YS, Bergson P, He WS, et al. Discovery of a small molecule that inhibits the interaction of anthrax edema factor with its cellular activator, calmodulin. Chem Biol 2004;11(8):1139-46
142. Schein CH, Chen D, Ma L, et al. Pharmacophore selection and redesign of non-nucleotide inhibitors of anthrax edema factor. Toxins 2012;4(11):1288-300
143. Chen D, Misra M, Sower L, et al. Novel inhibitors of anthrax edema factor. Bioorg Med Chem 2008;16(15):7225-33
144. Suryanarayana S, Wang JL, Richter M, et al. Distinct interactions of 2'-and 3'-O-(N-methyl)anthraniloyl-isomers of ATP and GTP with the adenylyl cyclase toxin of Bacillus anthracis, edema factor. Biochem Pharmacol 2009;78(3):224-30
145. Taha HM, Schmidt J, Gottle M, et al. Molecular analysis of the interaction of anthrax adenylyl cyclase toxin, edema factor, with 2'(3')-O-(N-(methyl) anthraniloyl)-substituted purine and pyrimidine nucleotides. Mol Pharmacol 2009;75(3):693-703
146. Pinto C, Lushington GH, Richter M, et al. Structure-activity relationships for the interactions of 2'-and 3'-(O)-(Nmethyl) anthraniloyl-substituted purine and pyrimidine nucleotides with mammalian adenylyl cyclases. Biochem Pharmacol 2011;82(4):358-70
147. Taha H, Dove S, Geduhn J, et al. Inhibition of the adenylyl cyclase toxin, edema factor, from Bacillus anthracis by a series of 18 mono-and bis-(M)ANTsubstituted nucleoside 5'-triphosphates. Naunyn Schmiedeberg's Arch Pharmacol 2012;385(1):57-68
148. Geduhn J, Dove S, Shen Y, et al. Bishalogen-anthraniloyl-substituted nucleoside 5'-triphosphates as potent and selective inhibitors of Bordetella pertussis adenylyl cyclase toxin. J Pharmacol Exp Ther 2011;336(1):104-15
149. Gille A, Lushington GH, Mou TC, et al. Differential inhibition of adenylyl cyclase isoforms and soluble guanylyl cyclase by purine and pyrimidine nucleotides. J Biol Chem 2004;279(19):19955-69
150. Laine E, Goncalves C, Karst JC, et al. Use of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis edema factor. Proc Natl Acad Sci USA 2010;107(25):11277-82