Development of Specific Therapy to Category A ToxicInfections

Cover Page

Abstract


Category A select agents continue to be major threat to human population both as naturally occurring diseases and as potential weapon of bioterrorists. Anthrax and botulism are probably the most threatening agents as both have virtually uncontrolled natural reservoirs from which they can be isolated and propagated. Available specific antitoxin therapy of both diseases is outdated; its efficiency is questionable as well as safety of reactogenic or human-derived components used in treatment. Highly sensitive toxin detection techniques are still not as widespread as it needed for timely alerting medical services. There is urgent need of pre-exposure prophylaxis and postexposure specific antitoxin therapy for anthrax and botulism. Analysis of modern studies in the field suggests oligoclonal antibodies acting against receptor-binding toxin subunits and nucleic acid aptamers as allosteric inhibitors of metlloproteolytic toxin components as the most promising candidates for development of efficient antitoxin therapy

A. V. Kolesnikov

State Research Center for Applied Microbiology & Biotechnology

Author for correspondence.
Email: pfu2000@mail.ru

Russian Federation Obolensk, Moscow Region

A. K. Ryabko

State Research Center for Applied Microbiology & Biotechnology

Email: ryabko_alena@mail.ru

Russian Federation Obolensk, Moscow Region

I. G. Shemyakin

State Research Center for Applied Microbiology & Biotechnology

Email: shemyakin@obolensk.org

Russian Federation Obolensk, Moscow Region

A. V. Kozyr

State Research Center for Applied Microbiology & Biotechnology

Email: avkozyr@gmail.com

Russian Federation Obolensk, Moscow Region

  1. Todar K. Bacterial Protein Toxins. Available at: http://textbookofbacteriology.net/proteintoxins.html (accessed: 10.05.2015).
  2. Proft T. Bacterial Toxins: Genetics, Cellular Biology and Practical Applications. Norfolk: Caister Academic Press. 2013. P. 234.
  3. Casadevall A., Pirofski L. Host-pathogen interactions: the attributes of virulence. J. Inf. Dis. 2001; 184 (3): 337–344.
  4. Montie T.C. Bacterial Protein Toxins. NY: Elsevier. 2013. Vol. 3. 109 р.
  5. Montal M. Botulinum neurotoxin: a marvel of protein design. Ann. Rev. Biochem. 2010; 79: 591–617.
  6. Mock M., Fouet A. Anthrax. Ann. Rev. Microbiol.2001; 55: 647–671.
  7. Brook I. Botulism: the challenge of diagnosis and treatment. Rev. Neurol. Dis. 2006; 3 (4): 182–189.
  8. Comer J.E., Ray B.D., Henning L.N., Stark G.V., Barnewall R.E., Mott J.M., Meister G.T. Characterization of a therapeutic model of inhalational anthrax using an increase in body temperature in New Zealand white rabbits as a trigger for treatment. Clin. Vaccine. Immunol. 2012; 19 (9): 1517–1525.
  9. Karwa M., Bronzert P., Kvetan V. Bioterrorism and critical care. Crit. Care Clin. 2003; 19 (2): 279–313.
  10. Rainey G.J., Young J.A. Antitoxins: novel strategies to target agents of bioterrorism. Nat. Rev. Microbiol. 2004; 2 (9): 721–726.
  11. Miyoshi S., Shinoda S. Bacterial metalloprotease as the toxic factor ininfection. Toxin Rev. 1997; 16 (4): 177–194.
  12. Hicks R.P., Hartell M.G., Nichols D.A., Bhattacharjee A.K., van Hamont J.E., Skillman D.R. The medicinal chemistry of botulinum, ricin and anthrax toxins. Curr. Med. Chem. 2005; 12 (6): 667–690.
  13. Liu S., Moayeri M., Leppla S.H. Anthrax lethal and edema toxins in anthrax pathogenesis. Trends Microbiol. 2014; 22 (6): 317–325.
  14. Jernigan D.B., Raghunathan P.L., Bell B.P., Brechner R., Bresnitz E.A., Butler J.C. Investigation of bioterrorism-related anthrax, United States, 2001: epidemiologic findings. Emerg. Infect. Dis. 2002; 8 (10): 1019–1028.
  15. Kaur M., Singh S., Bhatnagar R. Anthrax vaccines: present status and future prospects. Exp. Rev. Vaccines. 2013; 12 (8): 955–970.
  16. Baldari C.T., Tonello F., Paccani S.R., Montecucco C. Anthrax toxins: A paradigm of bacterial immune suppression. Trends Immunol. 2006; 27 (9): 434–440.
  17. 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.
  18. Chen Z., Moayeri M., Purcell R. Monoclonal antibody therapies against anthrax. Toxins (Basel). 2011; 3 (8): 1004–1019.
  19. Liu S., Zhang Y., Moayeri M., Liu J., Crown D., Fattah R.J., Wein A.N., Yu Z.X., Finkel T., Leppla S.H. Key tissue targets responsible for anthrax-toxin-induced lethality. Nature. 2013; 501 (7465): 63–68.
  20. Maize K.M., Kurbanov E.K., De La Mora-Rey T., Geders T.W., Hwang D.J., Walters M.A., Johnson R.L., Amin E.A., Finzel B.C. Anthrax toxin lethal factor domain 3 is highly mobile and responsive to ligand binding. Acta Crystallogr. Biol. Crystallogr. 2014; 70 (Pt. 11): 2813–2822.
  21. Tonello F., Ascenzi P., Montecucco C. The metalloproteolytic activity of the anthrax lethal factor is substrate-inhibited. J. Biol. Chem. 2003; 278 (41): 40075–40078.
  22. Levinsohn J.L., Newman Z.L., Hellmich K.A., Fattah R., Getz M.A., Liu S., Sastalla I., Leppla S.H., Moayeri M. Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLoS Pathog. 2012; 8 (3): 1002638.
  23. Banks D.J., Ward S.C., Bradley K.A. New insights into the functions of anthrax toxin. Exp. Rev. Mol. Med. 2006; 8 (7): 1–18.
  24. Nestorovich E.M., Bezrukov S.M. Designing inhibitors of anthrax toxin. Exp. Opin. Drug Discov. 2014; 9 (3): 299–318.
  25. Yao S. FDA NEWS RELEASE. FDA approves raxibacumab to treat inhalational anthrax. 2012. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm332341.html (accessed: 11.05.2015).
  26. Kummerfeldt C.E. Raxibacumab: potential role in the treatment of inhalational anthrax. Infect. Drug Resist. 2014; 7: 101–109.
  27. Chow S.K., Casadevall A. Monoclonal antibodies and toxins – a perspective on function and isotype. Toxins (Basel). 2012; 4 (6): 430–454.
  28. Malkevich N.V., Hopkins R.J., Bernton E., Meister G.T., Vela E.M., Atiee G., Johnson V., Nabors G.S., Aimes R.T., Ionin B., Skiadopoulos M.H. Efficacy and safety of AVP-21D9, an anthrax monoclonal antibody, in animal models and humans. Antimicrob. Agents Chemother. 2014; 58 (7): 3618–3625.
  29. Aulinger B.A., Roehrl M.H., Mekalanos J.J., Collier R.J., Wang J.Y. Сombining anthrax vaccine and therapy: a dominant-negative inhibitor of anthrax toxin is also a potent and safe immunogen for vaccines. Infect. Immun. 2005; 73 (6): 3408–3414.
  30. Vance D.J., Rong Y., Brey R.N., Mantis N.J. Combination of two candidate subunit vaccine antigens elicits protective immunity to ricin and anthrax toxin in mice. Vaccine. 2015; 33 (3): 417–421.
  31. Mechaly A., Levy H., Epstein E., Rosenfeld R., Marcus H., Ben-Arie E., Shafferman A., Ordentlich A., Mazor O. A novel mechanism for antibody-based anthrax toxin neutralization: inhibition of prepore-to-pore conversion. J. Biol. Chem. 2012; 287 (39): 32665–32673.
  32. Karginov V.A., Yohannes A., Robinson T.M., Fahmi N.E., Alibek K., Hecht S.M. Beta-cyclodextrin derivatives that inhibit anthrax lethal toxin. Bioorg. Med. Chem. 2006; 14 (1): 33–40.
  33. Lo S.Y., Säbel C.E., Webb M.I., Walsby C.J., Siemann S. High metal substitution tolerance of anthrax lethal factor and characterization of its active copper-substituted analogue. J. Inorg. Biochem. 2014; 140: 12–22.
  34. Kumar B.V., Malik S., Grandhi P., Dayam R., Sarma J.A. Anthrax lethal factor inhibitors as potential countermeasure of the infection. Curr. Top Med. Chem. 2014; 14 (17): 1977–1989.
  35. Abrami L., Brandi L., Moayeri M., Brown M.J., Krantz B.A., Leppla S.H., van der Goot F.G. Hijacking multivesicular bodies enables long-term and exosome-mediated long-distance action of anthrax toxin. Cell Rep. 2013; 5 (4): 986–996.
  36. Turk B.E. Discovery and development of anthrax lethal factor metalloproteinase inhibitors. Curr. Pharm. Biotechnol. 2008; 9 (1): 24–33.
  37. Bannwarth L., Goldberg A.B., Chen C., Turk B.E. Identification of exosite-targeting inhibitors of anthrax lethal factor by highthroughput screening. Chem. Biol. 2012; 19 (7): 875–882.
  38. Sela-Passwell N., Rosenblum G., Shoham T., Sagi I. Structural and functional bases for allosteric control of MMP activities: can it pave the path for selective inhibition? Biochim. Biophys. Acta. 2010; 1803 (1): 29–38.
  39. Jiao G.S., Kim S., Moayeri M., Cregar-Hernandez L., McKasson L., Margosiak S.A., Leppla S.H., Johnson A.T. 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): 6850–6853.
  40. Kim S., Jiao G.S., Moayeri M., Crown D., Cregar-Hernandez L., McKasson L., Margosiak S.A., Leppla S.H., Johnson A.T. Antidotes to anthrax lethal factor intoxication. Part 2: structural modifications leading to improved in vivo efficacy. Bioorg. Med. Chem. Lett. 2011; 21 (7): 2030–2033.
  41. Jiao G.S., Kim S., Moayeri M., Crown D., Thai A., Cregar-Hernandez L., McKasson L., Sankaran B., Lehrer A., Wong T., Johns L., Margosiak S.A., Leppla S.H., Johnson A.T. 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): 2242–2246.
  42. Rossetto O., Pirazzini M., Montecucco C. Botulinum neurotoxins: genetic, structural and mechanistic insights. Nat. Rev. Microbiol. 2014; 12 (8): 535–549.
  43. Levin B.R., Svanborg E.C. Selection and evolution of virulence in bacteria: an ecumenical excursion and modest suggestion. Parasitology. 1990; 100 (Suppl.): 103–115.
  44. Shilpa P.S., Kaul R., Sultana N., Bhat S. Botulinum toxin: The Midas touch. J. Nat. Sci. Biol. Med. 2014; 5(1): 8–14.
  45. Cavallini M., Cirillo P., Fundarò S.P., Quartucci S., Sciuto C., Sito G., Tonini D., Trocchi G., Signorini M. Safety of botulinum toxin A in aesthetic treatments: a systematic review of clinical studies. Dermatol. Surg. 2014; 40 (5): 525–536.
  46. Patel K., Cai S., Singh B.R. Current strategies for designing antidotes against botulinum neurotoxins. Expert Opin. Drug. Discov. 2014; 9 (3): 319–333.
  47. Nowakowski A., Wang C., Powers D.B., Amersdorfer P., Smith T.J., Montgomery V.A., Sheridan R., Blake R., Smith L.A., Marks J.D. Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody. Proc. Natl. Acad. Sci. USA. 2002; 99 (17): 11346–11350.
  48. Diamant E., Lachmi B.E., Keren A., Barnea A., Marcus H., Cohen S., David A.B., Zichel R. Evaluating the synergistic neutralizing effect of anti-botulinum oligoclonal antibody preparations. PLoS One. 2014; 9 (1): 87089.
  49. Chen C., Wang S., Wang H., Mao X., Zhang T., Ji G., Shi X., Xia T., Lu W., Zhang D., Dai J., Guo Y. Potent neutralization of botulinum neurotoxin/B by synergistic action of antibodies recognizing protein and ganglioside receptor binding domain. PLoS One. 2012; 7 (8): e43845.
  50. Whitemarsh R.C., Tepp W.H., Johnson E.A., Pellett S. Persistence of botulinum neurotoxin a subtypes 1–5 in primary rat spinal cord cells. PLoS One. 2014; 9 (2): 90252.
  51. Kiris E., Burnett J.C., Kane C.D., Bavari S. Recent advances in botulinum neurotoxin inhibitor development. Curr .Top Med. Chem. 2014; 14 (18): 2044–2061.
  52. Nestorovich E.M., Karginov V.A., Popoff M.R., Bezrukov S.M., Barth H. Tailored ß-cyclodextrin blocks the translocation pores of binary exotoxins from C. botulinum and C. perfringens and protects cells from intoxication. PLoS One. 2011; 6 (8): 23927.
  53. Lebeda F.J., Cer R.Z., Mudunuri U., Stephens R., Singh B.R., Adler M. The zinc-dependent protease activity of the botulinum neurotoxins. Toxins (Basel). 2010; 2 (5): 978–997.
  54. Turk B.E., Wong T.Y., Schwarzenbacher R., Jarrell E.T., Leppla S.H., Collier R.J., Liddington R.C., Cantley L.C. The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor. Nat. Struct. Mol. Biol. 2004; 11 (1): 60–66.
  55. Breidenbach M.A., Brunger A.T. Substrate recognition strategy for botulinum neurotoxin serotype A. Nature. 2004; 432 (7019): 925–929.
  56. Xue S., Javor S., Hixon M.S., Janda K.D. Probing BoNT/A protease exosites: implications for inhibitor design and light chain longevity. Biochemistry. 2014; 53 (43): 6820–6824.
  57. Sikorra S., Henke T., Galli T., Binz T.J. Substrate recognition mechanism of VAMP/synaptobrevin-cleaving clostridial neurotoxins. Biol. Chem. 2008; 283 (30): 21145–21152.
  58. Radom F., Jurek P.M., Mazurek M.P., Otlewski J., Jeleń F. Aptamers: molecules of great potential. Biotechnol. Adv. 2013; 31 (8): 1260–1274.
  59. McKeague M., Derosa M.C. Challenges and opportunities for s mall molecule aptamer development. J. Nucleic Acids. 2012; 2012: 748913.
  60. Dupont D.M., Andersen L.M., Botkjaer K.A., Andreasen P.A. Nucleic acid aptamers against proteases. Curr. Med. Chem. 2011; 18 (27): 4139–4151.
  61. Krauss I., Merlino A., Giancola C., Randazzo A., Mazzarella L., Sica F. Thrombin-aptamer recognition: a revealed ambiguity. Nucleic Acids Res. 2011; 39 (17): 7858–7867.
  62. Ni X., Castanares M., Mukherjee A., Lupold S.E. Nucleic acid aptamers: clinical applications and promising new horizons. Curr. Med. Chem. 2011; 18 (27): 4206–4214.
  63. Verghese J., Liang A., Sidhu P.P., Hindle M., Zhou Q., Desai U.R. First steps in the direction of synthetic, allosteric, direct inhibitors of thrombin and factor Xa. Bioorg. Med. Chem. Lett. 2009; 19 (15): 4126–4129.
  64. Radi M., Schenone S., Botta M. Allosteric inhibitors of Bcr-Abl: towards novel myristate-pocket binders. Curr. Pharm. Biotechnol. 2013; 14 (5): 477–487.
  65. Fukuda K., Umehara T., Sekiya S., Kunio K., Hasegawa T., Nishikawa S. An RNA ligand inhibits hepatitis C virus NS3 protease and helicase activities. Biochem. Biophys. Res. Commun. 2004; 325 (3): 670–675.
  66. Choi J.S., Kim S.G., Lahousse M., Park H.Y., Park H.C., Jeong B., Kim J., Kim S.K., Yoon M.Y. Screening and characterization of high-affinity ssDNAaptamers against anthrax protective antigen. J. Biomol. Screen. 2011; 16 (2): 266–271.
  67. Röder R., Wagner E. Sequence-defined shuttles for targeted nucleic acid and protein delivery. Ther. Deliv. 2014; 5 (9): 1025–1045.

Views

Abstract - 47

PDF (Russian) - 2

Cited-By


PlumX



Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.