Browse > Article
http://dx.doi.org/10.5483/BMBRep.2011.44.12.811

Identification of a lead small-molecule inhibitor of anthrax lethal toxin by using fluorescence-based high-throughput screening  

Wei, Dong (Beijing Center for Disease Control and Prevention)
Bu, Zhaoyun (The Peopl's Hospital of Rizhao City)
Yu, Ailian (Department of Aetiology and Institute of Aetiology, Taishan College of Medicine)
Li, Feng (Beijing Center for Disease Control and Prevention)
Publication Information
BMB Reports / v.44, no.12, 2011 , pp. 811-815 More about this Journal
Abstract
Inhalational anthrax is caused by B. anthracis, a virulent sporeforming bacterium which secretes anthrax toxins consisting of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease and is the main determinant in the pathogenesis of anthrax. Here we report the identification of a lead small-molecule inhibitor of anthrax lethal factor by screening an available synthetic small-molecule inhibitor library using fluorescence-based high-throughput screening (HTS) approach. Seven small molecules were found to have inhibitory effect against LF activity, among which SM157 had the highest inhibitory activity. All theses small molecule inhibitors inhibited LF in a noncompetitive inhibition mode. SM157 and SM167 are from the same family, both having an identical group complex, which is predicted to insert into S1' pocket of LF. More potent small-molecule inhibitors could be developed by modifying SM157 based on this identical group complex.
Keywords
B. anthracis; Fluorescence; Lethal toxin; Screening; Small-molecule inhibitor;
Citations & Related Records

Times Cited By Web Of Science : 0  (Related Records In Web of Science)
Times Cited By SCOPUS : 0
연도 인용수 순위
  • Reference
1 Shoop, W. L., Xiong, Y., Wiltsie, J., Woods, A., Guo, J., Pivnichny, J. V., Felcetto, T., Michael, B. F., Bansal, A., Cummings, R. T. Cunningham, B. R., Friedlander, A. M., Douglas, C. M., Patel, S. B., Wisniewski, D., Scapin, G., Salowe, S. P., Zaller, D. M., Chapman, K. T., Scolnick, E. M., Schmatz, D. M., Bartizal, K., MacCoss, M. and Hermes, J. D. (2005) Anthrax lethal factor inhibition. Proc. Natl. Acad. Sci. U.S.A. 102, 7958-7963.   DOI   ScienceOn
2 Peinado, J. R., Kacprzak, M. M., Leppla, S. H. and Lindberg, I. (2004) Cross-inhibition between furin and lethal factor inhibitors. Biochem. Bioph. Res. Co. 321, 601-605.   DOI   ScienceOn
3 Huber, M., Vor Dem, E. U., Grunow, R. and Bessler, W. G. (2005) Generation of mouse polyclonal and human monoclonal antibodies against Bacillus anthracis toxin. Drugs Exp. Clin. Res. 31, 35-43.
4 Mourez, M., Kane, R. S., Mogridge, J., Metallo, S., Deschatelets, P., Sellman, B. R., Whitesides, G. M. and Collier, R. J. (2001) Designing a polyvalent inhibitor of anthrax toxin. Nat. Biotechnol. 19, 958-961.   DOI   ScienceOn
5 Duesbery, N. S., Webb, C. P., Leppla, S. H., Gordon, V. M., Klimpel, K. R., Copeland, T. D., Ahn, N. G., Oskarsson, M. K., Fukasawa, K., Paull, K. D. and Vande Woude, G. F. (1998) Proteolytic inactivation of MAP kinase kinase by anthrax lethal factor. Science 280, 734-737.   DOI
6 Barrett, A. J., Rawlings, N. D. and Woessner, J. F. (2004) Introduction: metallopeptidases and their clans. in Handbook of proteolytic enzymes. Elsevier academic press, London, UK.
7 Turk, B. E., Wong, T. Y., Schwarzenbacher, R., Jarrell, E. T., Leppla, S. H., Collier, R. J., Liddington, R. C. and Cantley, L. C. (2004) The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor. Nat. Struct. Mol. Biol. 11, 60-66.   DOI   ScienceOn
8 Panchal, R. G., Hermone, A. R., Nguyen, T. L., Wong, T.Y. Schmidt, J., Lane, D., McGrath, C., Turk, B. E., Burnett, J., Aman, M. J., Little, S., Sausville, E. A., Zaharevitz, D. W., Cantley, L. C., Liddington, R. C., Gussio, R. and Bavari, S. (2004) Identification of small molecule inhibitors of anthrax lethal factor. Nat. Struct. Mol. Biol. 11, 67-72.   DOI   ScienceOn
9 Copeland, R. (2000) Enzymes: a practical introduction to structure, mechanism and data analysis (second edition). John Wiley & Sons, Inc., New York, USA.
10 Frazier, A. A., Franks, T. J. and Galvin, J. R. (2006) Inhalational anthrax. J. Thorac. Imaging 21, 252-258.   DOI   ScienceOn
11 Janeway, Jr., C. A. and Medzhitov. R. (2002) Innate immune recognition. Annu. Rev. Immunol. 20, 197-216.   DOI   ScienceOn
12 Pannifer, A. D., Wong, T. Y., Schwarzenbacher, R., Renatus, M., Petosa, C., Bienkowska, J., Lacy, D. B., Collier, R., Park, S., Leppla, H., Hunna, P. and Liddington, R. C. (2001) Crystal structure of the anthrax lethal factor. Nature 414, 229-233.   DOI   ScienceOn
13 Hanna, P., Acosta, D. and Collier, R. J. (1993) On the role of macrophages in anthrax. Proc. Natl. Acad. Sci. 90, 10198-10201.   DOI
14 Duesberya, N. S. and Vande Woudeb, G. F. (1999) Anthrax toxins. Cell. Mol. Life Sci. 55, 1599-1609.   DOI
15 Tournier, J. N., Quesnel-Hellmann, A., Cleret, A. and Vidal, D. R. (2007) Contribution of toxins to the pathogenesis of inhalational anthrax. Cellular Microbiology 9, 555-565.   DOI   ScienceOn
16 Boyden, E. D. and Dietrich, W. F. (2006) Nalp 1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nature Genetics 38, 240-244.   DOI   ScienceOn
17 Schepetkin, I. A., Khlebnikov, A. I., Kirpotina, L. N. and Quinn, M. T. (2006) Novel small-molecule inhibitors of anthrax lethal factor identified by high-throughput screening. J. Med. Chem. 49, 5232-5244.   DOI   ScienceOn
18 Turk, B. E. (2008) Discovery and development of anthrax lethal factor metalloprotease inhibitor. Curr. Pharm. Biotechno. 9, 24-33.   DOI   ScienceOn