Identification of a lead small-molecule inhibitor of anthrax lethal toxin by using fluorescence-based high-throughput screening
0
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
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. [BMB reports 2011; 44(12): 811-815]
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. [BMB reports 2011; 44(12): 811-815]
참고문헌 (18)
- Frazier, A. A, "Inhalational anthrax", J. Thorac. Imaging, 21, pp.252~258 (2006)
- Janeway, Jr., C. A, "Innate immune recognition", Annu. Rev. Immunol, 20, pp.197~216 (2002)
- Pannifer, A. D, "Crystal structure of the anthrax lethal factor", Nature, 414, pp.229~233 (2001)
- Hanna, P, "On the role of macrophages in anthrax", Proc. Natl. Acad. Sci, 90, pp.10198~10201 (1993)
- Tournier, J. N, "Contribution of toxins to the pathogenesis of inhalational anthrax", Cellular Microbiology, 90, pp.555~565 (2007)
- Boyden, E. D, "Nalp 1b controls mouse macrophage susceptibility to anthrax lethal toxin", Nature Genetics, 38, pp.240~244 (2006)
- Schepetkin, I. A, "Novel small-molecule inhibitors of anthrax lethal factor identified by high-throughput screening", J. Med. Chem, 49, pp.5232~5244 (2006)
- Duesberya, N. S, "Anthrax toxins", Cell. Mol. Life Sci, 55, pp.1599~1609 (1999)
- Turk, B. E, "Discovery and development of anthrax lethal factor metalloprotease inhibitor", Curr. Pharm. Biotechno, 9, pp.24~33 (2008)
- Peinado, J. R, "Cross-inhibition between furin and lethal factor inhibitors", Biochem. Bioph. Res. Co, 321, pp.601~605 (2004)
- Huber, M, "Generation of mouse polyclonal and human monoclonal antibodies against Bacillus anthracis toxin", Drugs Exp. Clin. Res, 31, pp.35~43 (2005)
- Mourez, M, "Designing a polyvalent inhibitor of anthrax toxin", Nat. Biotechnol, 19, pp.958~961 (2001)
- Duesbery, N. S, "Proteolytic inactivation of MAP kinase kinase by anthrax lethal factor", Science, 280, pp.734~737 (1998)
- Barrett, A. J, "Introduction: metallopeptidases and their clans. in Handbook of proteolytic enzymes" (2004), Elsevier academic press
- Turk, B. E, "The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor", Nat. Struct. Mol. Biol, 11, pp.60~66 (2004)
- Panchal, R. G, "Identification of small molecule inhibitors of anthrax lethal factor", Nat. Struct. Mol. Biol, 11, pp.67~72 (2004)
- Copeland, R, "Enzymes: a practical introduction to structure, mechanism and data analysis (second edition)" (2000), John Wiley & Sons
- Shoop, W. L, "Anthrax lethal factor inhibition", Proc. Natl. Acad. Sci. U.S.A, 102, pp.7958~7963 (2005)