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Engineering anthrax toxin variants that exclusively form octamers and their application to targeting tumors.

Abstract
Anthrax toxin protective antigen (PA) delivers its effector proteins into the host cell cytosol through formation of an oligomeric pore, which can assume heptameric or octameric states. By screening a highly directed library of PA mutants, we identified variants that complement each other to exclusively form octamers. These PA variants were individually nontoxic and demonstrated toxicity only when combined with their complementary partner. We then engineered requirements for activation by matrix metalloproteases and urokinase plasminogen activator into two of these variants. The resulting therapeutic toxin specifically targeted cells expressing both tumor associated proteases and completely stopped tumor growth in mice when used at a dose far below that which caused toxicity. This scheme for obtaining intercomplementing subunits can be employed with other oligomeric proteins and potentially has wide application.
AuthorsDamilola D Phillips, Rasem J Fattah, Devorah Crown, Yi Zhang, Shihui Liu, Mahtab Moayeri, Elizabeth R Fischer, Bryan T Hansen, Rodolfo Ghirlando, Ekaterina M Nestorovich, Alexander N Wein, Lacy Simons, Stephen H Leppla, Clinton E Leysath
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 13 Pg. 9058-65 (Mar 29 2013) ISSN: 1083-351X [Electronic] United States
PMID23393143 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References
  • Antigens, Bacterial
  • Bacterial Toxins
  • Proteins
  • anthrax toxin
Topics
  • Animals
  • Antigens, Bacterial (chemistry)
  • Bacillus anthracis (metabolism)
  • Bacterial Toxins (chemistry)
  • Cell Line, Tumor
  • Female
  • Gene Library
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Nude
  • Molecular Conformation
  • Mutation
  • Neoplasms (drug therapy, metabolism)
  • Plasmids (metabolism)
  • Protein Conformation
  • Protein Engineering (methods)
  • Protein Interaction Mapping (methods)
  • Protein Structure, Tertiary
  • Proteins (chemistry)
  • Ultracentrifugation

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