Lethal factor, anthrax

MA M34 M34.001 Anthrax lethal factor Component of anthrax toxin... 

The recruitment of zinc for a structural role, or to activate an enzyme, has been observed. The zinc ion induces the dimerization of human growth hormone (hGH), with two Zn ions associated per dimer of hGH. This is confirmed by replacement of possible zinc binding residues resulting in weakened binding of the zinc ion. Formation of a zinc-hGH dimeric complex may be important for storage of hGH in secretory granules.975 In a toxic role, anthrax lethal factor is one of the three components of the secreted toxin and is a zinc-dependent protease that cleaves a protein kinase and causes lysis of macrophages.976... 

A Ru-Josiphos catalyst was highly selective for the hydrogenation of an intermediate for an anthrax lethal factor inhibitor with a tetra-substituted C=C bond, as depicted in Figure 37.8 (Merck [44]). Rh-Josiphos (Lonza [42]) and Rh-Bo-Phoz (Eastman [45]) catalysts were effective for the hydrogenation of an exocy-clic and a cyclopropyl-substituted C=C bond. 

Anthrax lethal factor metalloproteinase (Table 1, entry 7) Anthrax lethal factor metalloproteinase is an integral component of the tripartite anthrax lethal toxin and is required for the onset and progression of anthrax. About 300 scaffolds were selected for an NMR-based assay leading to the carboxylic acid fragment 31 [42]. Subsequent synthetic elaboration led to nanomolar inhibitors such as 32. 

Recently, a SAMDI-MS assay was described by means of which endogenous caspase protease activities in cell lysates can be determined [26], Similar to the assay used to determine anthrax lethal factor inhibitors, peptide substrate SAMs for either caspase-3 or -8 were treated with cell lysates. In contrast to fluorescence assays, also longer peptide substrates could be used, thus enabling a better resolution of the two caspase activities. 

Min, D.H., Tang, W.J., Mrksich, M. Chemical screening by mass spectrometry to identify inhibitors of anthrax lethal factor. Nat. Biotcchnol. 2004, 22, 717-723. 

Melnyk R.A., Hewitt K.M., Lacy D.B., Lin H.C., Gessner C.R., Li S., Woods V.L. Jr, Collier R.J. Structural determinants for the binding of anthrax lethal factor to oligomeric protective antigen. J. Biol. Chem. 

Other Aminoglycoside Targets The Anthrax Lethal Factor 310... 

Key words Anthrax, Lethal factor, Metalloproteinases, Virtual screening, Docking and scoring,... 

Chopra AP, Boone S, Liang X et al (2003) Anthrax lethal factor proteolysis and inactivation of MAPK kinase. J Biol Chem 278 9402-9406... 

Vitale G, Bernardi L, Napolitani G et al (2000) Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J 352 739-745... 

Shoop WL, Xiong Y, Wiltsie J et al (2005) Anthrax lethal factor inhibition. Proc Natl Acad Sci USA 102 7958-7963... 

Panchal RG, Hermone AR, Nguyen TL et al (2004) Identification of small molecule inhibitors of anthrax lethal factor. Nat Struct Mol Biol 11 67-72... 

Yuan H, Johnson SL, Chen LH et al (2010) A novel pharmacophore model for the design of anthrax lethal factor inhibitors. Chem Biol Drug Des 76 263-268... 

Agrawal A, de Oliveira CA, Cheng Y et al (2009) Thioamide hydroxypyrothiones supersede amide hydroxypyrothiones in potency against anthrax lethal factor. J Med Chem 52 1063-1074... 

Roy J, Kumar UC, Machiraju PK et al (2010) In silico studies on anthrax lethal factor inhibitors pharmacophore modeling and virtual screening approaches towards designing of novel inhibitors for a killer. J Mol Graph Model 29 256-265... 

Koo, H.M., VanBrocklin, M., McWilliams, M.J., Leppla, S.H., Duesbery, N.S., Woude, G.F. (2002). Apoptosis and melano-genesis in human melanoma cells induced hy anthrax lethal factor inactivation of mitogen-activated rotein kinase kinase. Proc. Natl Acad. Sci USA 99 3052-7. 

Park, J.M., Greten, F.R., Li, Z.W., Karin, M. (2002). Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science 297 2048-51. 

Pellizzari, R., Guidi-Rontani, C., Vitale, G., Mock, M., Montecucco, C. (1999). Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNgamma-induced release of NO and TNFalpha. FEBS Lett. 462 199-204. 

Milne JC, Blanke SR, Hanna PC, Collier RJ (1995) Protective antigen-binding domain of anthrax lethal factor mediates translocation of a heterologous protein fused to its amino- or carboxy-terminus. Mol Microbiol 15 661 -666. 

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