Abstract
The term “toxin weapon” has been used to describe poisons, classically of natural origin but increasingly accessible by modern synthetic methods, which are suitable for delivery on a battlefield in a form that causes death or severe incapacitation at relatively low concentrations (reviewed in ref. 1). Several of the most important toxin weapons are proteins, and these molecules are the focus of this chapter. Recent technological changes have increased the importance of protein toxins for biological warfare (BW): (a) progress in biotechnology has made large-scale production and purification feasible for a larger number of protein toxins; (b) molecular biology techniques, especially the polymerase chain reaction, have enabled the identification, isolation and comparison of extended families of previously obscure natural toxins; and (c) gene manipulation and microbiology have greatly expanded the accessible delivery vehicles for protein toxins to include, for example, natural or genetically modified bacteria and engineered viruses.
Keywords
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Franz, D. R. (1997) Defense against toxin weapons, in Medical Aspects of Chemical and Biological Warfare (Sidell, F. R., Takafuji, E. T., and Franz, D. R., eds.), Office of the Surgeon General, Department of the Army, United States of America: Washington, D.C. pp. 603–620.
Gill, D. M. (1982) Bacterial toxins: a table of lethal amounts. Microbiol. Rev. 46(1), 86–94.
Hatheway, C. L. (1990) Toxigenic clostridia. Clin. Microbiol. Rev. 3(1), 66–98.
Paddle, B. M. (2003) Therapy and prophylaxis of inhaled biological toxins. J. Appl. Toxicol. 23(3), 139–170.
Dack, G. M. (1956) Food Poisoning. Third ed. The University of Chicago Press, Chicago, p. 251.
Morgan, J. C. and Bleck, T. P. (2002) Clinical aspects of tetanus, in Scientific and Therapeutic Aspects of Botulinum Toxin. (Brin, M. F., Jankovic, J., and Hallett, M., eds.), Lippincott Williams & Wilkins, Philadelphia, PA, pp. 151–164.
Newman, M. J. and Powell, M. F. (1995) Immunological and formulation design considerations for subunit vaccines, in Vaccin Design: The Subunit and Adjuvant Approach. (Powell, M. F. and Newman, M. J., eds.), Plenum Press, New York, pp. 1–42.
Mikszta, J. A., et al. (2002) Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery. Nat. Med. 8(4), 415–419.
Aoki, K. R. (2002) Physiology and pharmacology of therapeutic botulinum neurotoxins. Curr. Prob. Dermatol. 30, 107–116.
Jankovic, J. (2002) Botulinum toxin: clinical implications of antigenicity and immunoresistance, in Scientific and Therapeutic Aspects of Botulinum Toxin. (Brin, M. F., Jankovic, J., and Hallett, M., eds.), Lippincott Williams & Wilkins, Philadelphia, PA, 409–415.
Arnon, S. S., et al. (2001) Botulinum toxin as a biological weapon: medical and public health management. JAMA 285(8), 1059–1070.
Simpson, L. L. (1981) The origin, structure, and pharmacological activity of botulinum toxin. Pharmacol. Rev. 33(3), 155–188.
Shapiro, R. L., Hatheway, C., and Swerdlow, D. L. (1998) Botulism in the United States: a clinical and epidemiologic review. Ann. Intern. Med. 129(3), 221–228.
Franz, D. R., Parrott, C. D., and Takafuji, E. T. (1997) The U. S. Biological Warfare and Biological Defense Programs, in Medical Aspects of Chemical and Biological Warfare (Sidell, F. R., Takafuji, E. T., and Franz, D. R., eds.), Office of the Surgeon General, Department of the Army, United States of America, Washington, D.C., pp. 425–436.
Umland, T. C., et al. (1997) Structure of the receptor binding fragment HC of tetanus neurotoxin. Nat. Struct. Biol. 4(10), 788–792.
Lacy, D. B., et al. (1998) Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat. Struct. Biol. 5(10), 898–902.
Lacy, D. B. and Stevens, R. C. (1999) Sequence homology and structural analysis of the clostridial neurotoxins. J. Mol. Biol. 291(5), 1091–1104.
Eswaramoorthy, S., Kumaran, D., and Swaminathan, S. (2001) Crystallographic evidence for doxorubicin binding to the receptor-binding site in Clostridium botulinum neurotoxin B. Acta Crystallogr. D Biol. Crystallogr. 57(Pt 11), 1743–1746.
Montecucco, C. (1986) How do tetanus and botulinum toxins bind to neuronal membranes? Trends Biochem. Sci. 11, 314–317.
Fujinaga, Y., et al. (1997) The haemagglutinin of Clostridium botulinum type C progenitor toxin plays an essential role in binding of toxin to the epithelial cells of guinea pig small intestine, leading to the efficient absorption of the toxin. Microbiology 143(Pt 12), 3841–3847.
Koriazova, L. K. and Montal, M. (2003) Translocation of botulinum neurotoxin light chain protease through the heavy chain channel. Nat. Struct. Biol. 10(1), 13–18.
Sheridan, R. E. (1998) Gating and permeability of ion channels produced by botulinum toxin types A and E in PC12 cell membranes. Toxicon 36(5), 703–717.
Simpson, L. L. (1986) Molecular pharmacology of botulinum toxin and tetanus toxin. Annu. Rev. Pharmacol. Toxicol. 26, 427–453.
Poulain, B., et al. (1991) Heterologous combinations of heavy and light chains from botulinum neurotoxin A and tetanus toxin inhibit neurotransmitter release in Aplysia. J. Biol. Chem. 266(15), 9580–9585.
Hanson, P. I., Heuser, J. E., and Jahn, R. (1997) Neurotransmitter release—four years of SNARE complexes. Curr. Opin. Neurobiol. 7(3), 310–315.
Brunger, A. T. (2001) Structure of proteins involved in synaptic vesicle fusion in neurons. Annu. Rev. Biophys. Biomol. Struct. 30, 157–171.
Rizo, J. (2003) SNARE function revisited. Nat. Struct. Biol. 10(6), 417–419.
Reames, H. R., et al. (1947) Studies on botulinum toxoids, types A and B III. Immunization in man. J. Immunol. 55, 309–324.
Sterne, M. and Wentzel, L. M. (1950) A new method for the large-scale production of high-titre botulinum formol-toxoid types C and D. J. Immunol. 65, 175–183.
Fiock, M. A., Cardella, M. A., and Gearinger, N. F. (1963) Studies of immunities to toxins of Clostridium botulinum. IX. Immunologic response of man to purified pentavalent ABCDE botulinum toxoid. J. Immunol. 90, 697–702.
Cardella, M. A. (1964) Botulinum toxoids, in Botulism, Proceedings of a Symposium. U. S. Public Health Service Publication No. 999-FP-1. (Lewis, Jr., K. H. a. C., ed.), Public Health Service, Cincinnati, OH, pp. 113–130.
Anderson, J. H. and Lewis, G. E. (1981) Clinical evaluation of botulinum toxoids, in Biomedical Aspects of Botulism. (Lewis, G. E., ed.), Academic Press, New York, pp. 233–246.
Oguma, K., Fujinaga, Y., and Inoue, K. (1995) Structure and function of Clostridium botulinum toxins. Microbiol. Immunol. 39(3), 161–168.
Siegel, L. S. (1988) Human immune response to botulinum pentavalent (ABCDE) toxoid determined by a neutralization test and by an enzyme-linked immunosorbent assay. J. Clin. Microbiol. 26(11), 2351–2356.
Hatheway, C. (1976) Toxoid of Clostridium botulinum type F: purification and immunogenicity studies. Appl. Environ. Microbiol. 31, 234–242.
Torii, Y., et al. (2002) Production and immunogenic efficacy of botulinum tetravalent (A, B, E, F) toxoid. Vaccine 20(19–20), 2556–2561.
Byrne, M. P. and Smith, L. A. (2000) Development of vaccines for prevention of botulism. Biochimie 82(9–10), 955–966.
Fairweather, N. F., Lyness, V. A., and Maskell, D. J. (1987) Immunization of mice against tetanus with fragments of tetanus toxin synthesized in Escherichia coli. Infect. Immun. 55(11), 2541–2545.
Clayton, M. A., et al. (1995) Protective vaccination with a recombinant fragment of Clostridium botulinum neurotoxin serotype A expressed from a synthetic gene in Escherichia coli. Infect. Immun. 63(7), 2738–2742.
LaPenotiere, H. F., Clayton, M. A., and Middlebrook, J. L. (1995) Expression of a large, nontoxic fragment of botulinum neurotoxin serotype A and its use as an immunogen. Toxicon 33(10), 1383–1386.
Simpson, L. L. (1984) Fragment C of tetanus toxin antagonizes the neuromuscular blocking properties of native tetanus toxin. J. Pharmacol. Exp. Ther. 228(3), 600–604.
Simpson, L. L. (1984) Botulinum toxin and tetanus toxin recognize similar membrane determinants. Brain Res. 305(1), 177–180.
Helting, T. B. and Nau, H. H. (1984) Analysis of the immune response to papain digestion products of tetanus toxin. Acta Pathol. Microbiol. Immunol. Scand. (C) 92(1), 59–63.
Thompson, D. E., et al. (1990) The complete amino acid sequence of the Clostridium botulinum type A neurotoxin, deduced by nucleotide sequence analysis of the encoding gene. Eur. J. Biochem. 189(1), 73–81.
Dertzbaugh, M. T. and West, M. W. (1996) Mapping of protective and cross-reactive domains of the type A neurotoxin of Clostridium botulinum. Vaccine 14(16), 1538–1544.
Middlebrook, J. L. (1995) Protection strategies against botulinum toxin. Adv. Exp. Med. Biol. 383, 93–98.
Potter, K. J., et al. (1998) Production and purification of the heavy-chain fragment C of botulinum neurotoxin, serotype B, expressed in the methylotrophic yeast Pichia pastoris. Protein Expr. Purif. 13(3), 357–365.
Byrne, M. P., et al. (1998) Purification, potency, and efficacy of the botulinum neurotoxin type A binding domain from Pichia pastoris as a recombinant vaccine candidate. Infect. Immun. 66(10), 4817–4822.
Byrne, M. P., et al. (2000) Fermentation, purification, and efficacy of a recombinant vaccine candidate against botulinum neurotoxin type F from Pichia pastoris. Protein Expr. Purif. 18(3), 327–337.
Potter, K. J., et al. (2000) Production and purification of the heavy chain fragment C of botulinum neurotoxin, serotype A, expressed in the methylotrophic yeast Pichia pastoris. Protein Expr. Purif. 19(3), 393–402.
Woodward, L. A., et al. (2003) Expression of HC subunits from Clostridium botulinum types C and D and their evaluation as candidate vaccine antigens in mice. Infect. Immun. 71(5), 2941–2944.
Bouvier, A., et al. (2003) Identifying and modulating disulfide formation in the biopharmaceutical production of a recombinant protein vaccine candidate. J. Biotechnol. 103(3), 257–271.
Atassi, M. Z. (2002) Immune recognition and cross-reactivity of botulinum neurotoxins, in Scientific and Therapeutic Aspects of Botulinum Toxin. (Brin, M. F., Jankovic, J., and Hallett, M., eds.), Lippincott, Williams & Wilkins, Philadelphia, PA, pp. 385–408.
Swaminathan, S. and Eswaramoorthy, S. (2000) Structural analysis of the catalytic and binding sites of Clostridium botulinum neurotoxin B. Nat. Struct. Biol. 78), 693–699.
Chaddock, J. A., et al. (2002) Expression and purification of catalytically active, nontoxic endopeptidase derivatives of Clostridium botulinum toxin type A. Protein Expr. Purif. 25(2), 219–228.
Lee, J. S., et al. (2001) Candidate vaccine against botulinum neurotoxin serotype A derived from a Venezuelan equine encephalitis virus vector system. Infect. Immun. 69(9), 5709–5715.
Park, J. B. and Simpson, L. L. (2003) Inhalational poisoning by botulinum toxin and inhalation vaccination with its heavy-chain component. Infect. Immun. 71(3), 1147–1154.
Bennett, A. M., Perkins, S. D., and Holley, J. L. (2003) DNA vaccination protects against botulinum neurotoxin type F. Vaccine 21(23), 3110–3117.
Foynes, S., et al. (2003) Vaccination against type F botulinum toxin using attenuated Salmonella enterica var Typhimurium strains expressing the BoNT/F H(C) fragment. Vaccine 21(11–12), 1052–1059.
Kiyatkin, N., Maksymowych, A. B., and Simpson, L. L. (1997) Induction of an immune response by oral administration of recombinant botulinum toxin. Infect. Immun. 65(11), 4586–4591.
Simpson, L. L., Maksymowych, A. B., and Kiyatkin, N. (1999) Botulinum toxin as a carrier for oral vaccines. Cell Mol. Life Sci. 56(1–2), 47–61.
Zdanovsky, A. G. and Zdanovskaia, M. V. (2000) Simple and efficient method for heterologous expression of clostridial proteins. Appl. Environ. Microbiol. 66(8), 3166–3173.
Bradshaw, M., Goodnough, M. C., and Johnson, E. A. (1998) Conjugative transfer of the Escherichia coli-Clostridium perfringens shuttle vector pJIR1457 to Clostridium botulinum type A strains. Plasmid 40(3), 233–237.
Pless, D. D., et al. (2001) High-affinity, protective antibodies to the binding domain of botulinum neurotoxin type A. Infect. Immun. 69(1), 570–574.
Amersdorfer, P., et al. (1997) Molecular characterization of murine humoral immune response to botulinum neurotoxin type A binding domain as assessed by using phage antibody libraries. Infect. Immun. 65(9), 3743–3752.
Amersdorfer, P., et al. (2002) Genetic and immunological comparison of anti-botulinum type A antibodies from immune and non-immune human phage libraries. Vaccine 20(11–12), 1640–1648.
Nowakowski, A., et al. (2002) Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody. Proc. Natl. Acad. Sci. USA 99(17), 11,346–11,350.
Kuroiwa, Y., et al. (2002) Cloned transchromosomic calves producing human immunoglobulin. Nat. Biotechnol. 20(9), 889–894.
Adler, M., et al. (1994) Evaluation of captopril and other potential therapeutic compounds in antagonizing botulinum toxin-induced muscle paralysis, in Therapy with Botulinum Toxin (Jankovic, J. and Hallett, M., eds.), Marcel Dekker, New York, pp. 63–70.
Adler, M., et al. (1998) Efficacy of a novel metalloprotease inhibitor on botulinum neurotoxin B activity. FEBS Lett. 429(3), 234–238.
Schmidt, J. J., Stafford, R. G., and Millard, C. B. (2001) High-throughput assays for botulinum neurotoxin proteolytic activity: serotypes A, B, D, and F. Anal. Biochem. 296(1), 130–137.
Schmidt, J. J. and Stafford, R. G. (2002) A high-affinity competitive inhibitor of type A botulinum neurotoxin protease activity. FEBS Lett. 532(3), 423–426.
Anne, C., et al. (2003) Development of potent inhibitors of botulinum neurotoxin type B. J. Med. Chem. 46(22), 4648–4656.
Anne, C., et al. (2003) Thio-derived disulfides as potent inhibitors of botulinum neurotoxin type B: implications for zinc interaction. Bioorg. Med. Chem. 11(21), 4655–4660.
Zou, J., et al. (1985) The effect of toosendanin on monkey botulism. J. Tradit. Chin. Med. 5(1), 29, 30.
Wang, Z. F. and Shi, Y. L. (2001) Toosendanin-induced inhibition of small-conductance calcium-activated potassium channels in CA1 pyramidal neurons of rat hippocampus. Neurosci. Lett. 303(1), 13–16.
Xu, Y. and Shi, Y. (1993) Action of toosendanin on the membrane current of mouse motor nerve terminals. Brain Res. 631(1), 46–50.
Shih, Y. L. (1986) Abolishment of non-quantal release of acetylcholine from the mouse phrenic nerve endings by toosendanin. Jpn. J. Physiol. 36(3), 601–605.
Ding, J., Xu, T. H., and Shi, Y. L. (2001) Different effects of toosendanin on perineurially recorded Ca(2+) currents in mouse and frog motor nerve terminals. Neurosci. Res. 41(3), 243–249.
Adler, M., et al. (1996) Effect of 3,4-diaminopyridine on rat extensor digitorum longus muscle paralyzed by local injection of botulinum neurotoxin. Toxicon 34(2), 237–249.
Adler, M., Capacio, B., and Deshpande, S. S. (2000) Antagonism of botulinum toxin Amediated muscle paralysis by 3, 4-diaminopyridine delivered via osmotic minipumps. Toxicon 38(10), 1381–1388.
O’Sullivan, G. A., et al. (1999) Rescue of exocytosis in botulinum toxin A-poisoned chromaffin cells by expression of cleavage-resistant SNAP-25. Identification of the minimal essential C-terminal residues. J. Biol. Chem. 274(52), 36,897–36,904.
Ulrich, R. G., Bavari, S., and Olson, M. A. (1995) Bacterial superantigens in human disease: structure, function and diversity. Trends Microbiol. 3(12), 463–468.
Spero, L., Johnson-Winegar, A., and Schmidt, J. J. (1988) Enterotoxins of Staphylococci, in Bacterial Toxins: Handbook of Natural Toxins (Hardegree, M. C. and Tu, A. T. eds.), Marcel Dekker, New York, pp. 131–163.
Bohach, G. A., et al. (1996) The staphylococcal and streptococcal pyrogenic toxin family. Adv. Exp. Med. Biol. 391, 131–154.
Sundberg, E. J., Li, Y., and Mariuzza, R. A. (2002) So many ways of getting in the way: diversity in the molecular architecture of superantigen-dependent T-cell signaling complexes. Curr. Opin. Immunol. 14(1), 36–44.
Dinges, M. M., Orwin, P. M., and Schlievert, P. M. (2000) Exotoxins of Staphylococcus aureus. Clin. Microbiol. Rev. 13(1), 16–34, table of contents.
Ulrich, R. G. (2000) Evolving superantigens of Staphylococcus aureus. FEMS Immunol. Med. Microbiol. 27(1), 1–7.
Swaminathan, S., et al. (1988) Crystallization and preliminary X-ray study of staphylococcal enterotoxin B. J. Mol. Biol. 199(2), 397.
Swaminathan, S., et al. (1992) Crystal structure of staphylococcal enterotoxin B, a superantigen. Nature 359(6398), 801–806.
Swaminathan, S., et al. (1995) Residues defining V beta specificity in staphylococcal enterotoxins. Nat. Struct. Biol. 2(8), 680–686.
Krakauer, T. (1999) Immune response to staphylococcal superantigens. Immunol. Res. 20, 163–173.
Ulrich, R. G., et al. (1997) Staphylococcal enterotoxin B and related pyrogenic toxins, in Medical Aspects of Chemical and Biological Warfare (Sidell, F. R., Takafuji, E. T., and Franz, D. R., eds.), Office of the Surgeon General, Department of the Army, United States of America, Washington, D.C., pp. 621–630.
Schantz, E. J., et al. (1965) Purification of staphylococcal enterotoxin B. Biochemistry 4, 1011–1016.
McGann, V. G. (1969) Evaluation of immunity against staphylococcal enterotoxin B. Commission on Epidemiological Survey, Annual Report to the Armed Forces.
McGann, V. G., et al. (1970) Immunological studies with microbial toxins. Research and Techology Work Unit Summary. Annual Progress Report. U. S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD.
Denniston, J. C., et al. (1970) Hypersensitivity reaction to staphylococcal enterotoxin B. Commission on Eppidemiological Survey. Annual Report to the Armed Forces Epidemiological Board FY 1970. Fort Detrick, MD.
Warren, J. R., Spero, L., and Metzger, J. F. (1974) The pH dependence of enterotoxin polymerization by formaldehyde. Biochim. Biophys. Acta 365(2), 434–438.
Warren, J. R., et al. (1975) Immunogenicity of formaldehyde-inactivated enterotoxins A and C1 of Staphylococcus aureus. J. Infect. Dis. 131(5), 535–542.
Tseng, J., et al. (1993) Immunity and responses of circulating leukocytes and lymphocytes in monkeys to aerosolized staphylococcal enterotoxin B. Infect. Immun. 61(2), 391–398.
Tseng, J., et al. (1995) Humoral immunity to aerosolized staphylococcal enterotoxin B (SEB), a superantigen, in monkeys vaccinated with SEB toxoid-containing microspheres. Infect. Immun. 63(8), 2880–2885.
Lowell, G. H., et al. (1996) Immunogenicity and efficacy against lethal aerosol staphylococcal enterotoxin B challenge in monkeys by intramuscular and respiratory delivery of proteosome-toxoid vaccines. Infect. Immun. 64(11), 4686–4693.
Lowell, G. H., et al. (1996) Intranasal and intramuscular proteosome-staphylococcal enterotoxin B (SEB) toxoid vaccines: immunogenicity and efficacy against lethal SEB intoxication in mice. Infect. Immun. 64(5), 1706–1713.
Ulrich, R. G., Olson, M. A., and Bavari, S. (1998) Development of engineered vaccines effective against structurally related bacterial superantigens. Vaccine 16(19), 1857–1864.
Ulrich, R. G., Bavari, S., and Olson, M. A. (1995) Staphylococcal enterotoxins A and B share a common structural motif for binding class II major histocompatibility complex molecules. Nat. Struct. Biol. 2(7), 554–560.
Leder, L., et al. (1998) A mutational analysis of the binding of staphylococcal enterotoxins B and C3 to the T cell receptor beta chain and major histocompatibility complex class II. J. Exp. Med. 187(6), 823–833.
Olson, M. A. and Cuff, L. (1997) Molecular docking of superantigens with class II major histocompatibility complex proteins. J. Mol. Recognit. 10(6), 277–289.
Woody, M. A., et al. (1998) Differential immune responses to staphylococcal enterotoxin B mutations in a hydrophobic loop dominating the interface with major histocompatibility complex class II receptors. J. Infect. Dis. 177(4), 1013–1022.
Krupka, H. I., et al. (2002) Structural basis for abrogated binding between staphylococcal enterotoxin A superantigen vaccine and MHC-IIalpha. Protein Sci. 11(3), 642–651.
DaSilva, L., et al. (2002) Humanlike immune response of human leukocyte antigen-DR3 transgenic mice to staphylococcal enterotoxins: a novel model for superantigen vaccines. J. Infect Dis. 185(12), 1754–1760.
Coffman, J. D., et al. (2002) Production and purification of a recombinant Staphylococcal enterotoxin B vaccine candidate expressed in Escherichia coli. Protein Expr. Purif. 24(2), 302–312.
Bavari, S., Dyas, B., and Ulrich, R. G. (1996) Superantigen vaccines: a comparative study of genetically attenuated receptor-binding mutants of staphylococcal enterotoxin A. J. Infect. Dis. 174(2), 338–345.
Nilsson, I. M., et al. (1999) Protection against Staphylococcus aureus sepsis by vaccination with recombinant staphylococcal enterotoxin A devoid of superantigenicity. J. Infect. Dis. 180(4), 1370–1373.
Swietnicki, W., et al. (2003) Zinc Binding and dimerization of streptococcus pyogenes pyrogenic exotoxin C are not essential for T-cell stimulation. J. Biol. Chem. 278(11), 9885–9895.
Krakauer, T. and Buckley, M. (2003) Doxycycline is anti-inflammatory and inhibits staphylococcal exotoxin-induced cytokines and chemokines. Antimicrob. Agents Chemother. 47(11), 3630–3633.
Krakauer, T., Li, B. Q., and Young, H. A. (2001) The flavonoid baicalin inhibits superantigen-induced inflammatory cytokines and chemokines. FEBS Lett. 500(1-2), 52–55.
Krakauer, T. (2001) Suppression of endotoxin-and staphylococcal exotoxin-induced cytokines and chemokines by a phospholipase C inhibitor in human peripheral blood mononuclear cells. Clin. Diagn. Lab. Immunol. 8(2), 449–453.
Cope, A. C. (1946) Chapter 12: Ricin in Summary technical report of Division 9 on Chemical warfare and related problems: Parts I-II. National Defense Research Committee, Office of Scientific Research and Development, Washington DC, pp. 179–203.
Knight, B. (1979) Ricin—a potent homicidal poison. Br. Med. J. 1(6159), 350, 351.
Hewetson, J. F., et al. (1993) Protection of mice from inhaled ricin by vaccination with ricin or by passive treatment with heterologous antibody. Vaccine 11(7), 743–746.
Griffiths, G. D., et al. (1996) The inhalation toxicology of the castor bean toxin, ricin, and protection by vaccination. J. Defense Sci. 1(2), 227–235.
Crompton, R. and Gall, D. (1980) Georgi Markov—death in a pellet. Med. Leg. J. 48(2), 51–62.
Franz, D. R. and Jaax, N. K. (1997) Ricin toxin, in Medical Aspects of Chemical and Biological Warfare (Sidell, F. R., Takafuji, E. T., and Franz, D. R., eds.), Office of the Surgeon General, Department of the Army, United States of America, Washington, D.C., pp. 631–642.
Robertus, J. (1991) The structure and action of ricin, a cytotoxic N-glycosidase. Semin. Cell Biol. 2(1), 23–30.
Lord, J. M., Hartley, M. R., and Roberts, L. M. (1991) Ribosome inactivating proteins of plants. Semin. Cell Biol. 2(1), 15–22.
Obrig, T. G. (1994) Toxins that inhibit host protein synthesis. Methods Enzymol. 235, 647–656.
Balint, G. A. (1974) Ricin: the toxic protein of castor oil seeds. Toxicology 2(1), 77–102.
Brugsch, H. G. (1960) Toxic hazards: The castor bean. Mass. Med. Soc. 262(1039-1040).
Wilhelmsen, C. L. and Pitt, M. L. (1996) Lesions of acute inhaled lethal ricin intoxication in rhesus monkeys. Vet. Pathol. 33(3), 296–302.
Griffiths, G. D., Phillips, G. J., and Bailey, S. C. (1999) Comparison of the quality of protection elicited by toxoid and peptide liposomal vaccine formulations against ricin as assessed by markers of inflammation. Vaccine 17(20–21), 2562–2568.
Ghetie, V. and Vitetta, E. (1994) Immunotoxins in the therapy of cancer: from bench to clinic. Pharmacol. Ther. 63(3), 209–234.
Vitetta, E. S., Thorpe, P. E., and Uhr, J. W. (1993) Immunotoxins: magic bullets or misguided missiles? Trends Pharmacol. Sci. 14(5), 148–154.
Soler-Rodriguez, A. M., et al. (1992) The toxicity of chemically deglycosylated ricin Achain in mice. Int. J. Immunopharmacol. 14(2), 281–291.
Lord, J. M., et al. (1987) Ricin: cytotoxicity, biosynthesis and use in immunoconjugates. Prog. Med. Chem. 24, 1–28.
Lemley, P. V. and Creasia, D. A. (1995) Vaccine against ricin toxin, in U. S. Patent & Trademark Office. United States of America, Secretary of the Army, Washington, DC.
Lemley, P. V. and Wright, D. C. (1992) Mice are actively immunized after passive monoclonal antibody prophylaxis and ricin toxin challenge. Immunology 76(3), 511–513.
Aboud-Pirak, E., et al. (1993) Identification of a neutralizing epitope on ricin a chain and application of its 3D structure to design peptide vaccines that protect against ricin intoxication, in 1993 Medical Defense Bioscience Review. U. S. Army Medical Research & Materiel Command, Baltimore, MD.
Griffiths, G. D., et al. (1998) Local and systemic responses against ricin toxin promoted by toxoid or peptide vaccines alone or in liposomal formulations. Vaccine 16(5), 530–535.
Smallshaw, J. E., et al. (2002) A novel recombinant vaccine which protects mice against ricin intoxication. Vaccine 20(27–28), 3422–3427.
Olson, M. A. (1997) Ricin A-chain structural determinant for binding substrate analogues: a molecular dynamics simulation analysis. Proteins 27(1), 80–95.
Olson, M. A. and Cuff, L. (1999) Free energy determinants of binding the rRNA substrate and small ligands to ricin A-chain. Biophys. J. 76(1 Pt 1), 28–39.
Olson, M. A. (2001) Electrostatic effects on the free-energy balance in folding a ribosome-inactivating protein. Biophys. Chem. 91(3), 219–229.
Tanaka, K. S., et al. (2001) Ricin A-chain inhibitors resembling the oxacarbenium ion transition state. Biochemistry 40(23), 6845–6851.
Miller, D. J., et al. (2002) Structure-based design and characterization of novel platforms for ricin and shiga toxin inhibition. J. Med. Chem. 45(1), 90–98.
Hopkins, A. L. and Groom, C. R. (2002) The druggable genome. Nat. Rev. Drug Discov. 1(9), 727–730.
Finkel, E. (2001) Australia. Engineered mouse virus spurs bioweapon fears. Science 291(5504), 585.
Landgraf, R., et al. (1998) Cytotoxicity and specificity of directed toxins composed of diphtheria toxin and the EGF-like domain of heregulin beta1. Biochemistry 37(9), 3220–3228.
vanderSpek, J. C. and Murphy, J. R. (2000) Fusion protein toxins based on diphtheria toxin: selective targeting of growth factor receptors of eukaryotic cells. Methods Enzymol. 327, 239–249.
Francis, J. W., et al. (2000) Enhancement of diphtheria toxin potency by replacement of the receptor binding domain with tetanus toxin C-fragment: a potential vector for delivering heterologous proteins to neurons. J. Neurochem. 74(6), 2528–2536.
Fisher, C. E., et al. (1996) Genetic construction and properties of a diphtheria toxin-related substance P fusion protein: in vitro destruction of cells bearing substance P receptors. Proc. Natl. Acad. Sci. USA 93(14), 7341–7345.
Arora, N., et al. (1994) Cytotoxic effects of a chimeric protein consisting of tetanus toxin light chain and anthrax toxin lethal factor in non-neuronal cells. J. Biol. Chem. 269(42), 26,165–26,171.
Arora, N. and Leppla, S. H. (1994) Fusions of anthrax toxin lethal factor with shiga toxin and diphtheria toxin enzymatic domains are toxic to mammalian cells. Infect. Immun. 62(11), 4955–4961.
Walev, I., et al. (2001) Delivery of proteins into living cells by reversible membrane permeabilization with streptolysin-O. Proc. Natl. Acad. Sci USA 98(6), 3185–3190.
Ohno, M., et al. (1998) Molecular evolution of snake toxins: is the functional diversity of snake toxins associated with a mechanism of accelerated evolution? Prog. Nucleic Acid Res. Mol. Biol. 59, 307–364.
Le Du, M. H., et al. (2000) Stability of a structural scaffold upon activity transfer: X-ray structure of a three fingers chimeric protein. J. Mol. Biol. 296(4), 1017–1026.
Harel, M., et al. (1995) Crystal structure of an acetylcholinesterase-fasciculin complex: interaction of a three-fingered toxin from snake venom with its target. Structure 3(12), 1355–1366.
Meves, H., Simard, J. M., and Watt, D. D. (1986) Interactions of scorpion toxins with the sodium channel, in Tetrodotoxin, Saxitoxin, and The Molecular Biology of the Sodium Channel (Yao, C. Y. and Levinson, S. R., eds.), The New York Academy of Sciences, New York, NY, pp. 113–132.
Zilberberg, N., et al. (1996) Functional expression and genetic alteration of an alpha scorpion neurotoxin. Biochemistry 35(31), 10,215–10,222.
Bouhaouala-Zahar, B., et al. (2000) A chimeric scorpion alpha-toxin displays de novo electrophysiological properties similar to those of alpha-like toxins. Eur. J. Biochem. 269(12), 2831–2841.
Olivera, B. M., et al. (1985) Peptide neurotoxins from fish-hunting cone snails. Science 230(4732), 1338–1343.
Broomfield, C. A., Lockridge, O., and Millard, C. B. (1999) Protein engineering of a human enzyme that hydrolyzes V and G nerve agents: design, construction and characterization. Chem. Biol. Interact. 119–120, 413–418.
Sun, H., et al. (2002) Cocaine metabolism accelerated by a re-engineered human butyrylcholinesterase. J. Pharmacol. Exp. Ther. 302(2), 710–716.
Lacy, D. B. and Stevens, R. C. (1998) Unraveling the structures and modes of action of bacterial toxins. Curr. Opin. Struct. Biol. 8(6), 778–784.
Gerstein, M. (2000) Integrative database analysis in structural genomics. Nat. Struct. Biol. 7(Suppl.), 960–963.
Gerstein, M., et al. (2003) Structural genomics: current progress. Science 299(5613), 1663.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Humana Press Inc., Totowa, NJ
About this chapter
Cite this chapter
Millard, C.B. (2005). Medical Defense Against Protein Toxin Weapons. In: Lindler, L.E., Lebeda, F.J., Korch, G.W. (eds) Biological Weapons Defense. Infectious Disease. Humana Press. https://doi.org/10.1385/1-59259-764-5:255
Download citation
DOI: https://doi.org/10.1385/1-59259-764-5:255
Publisher Name: Humana Press
Print ISBN: 978-1-58829-184-4
Online ISBN: 978-1-59259-764-2
eBook Packages: MedicineMedicine (R0)