Tumor endothelium marker-8 based decoys exhibit superiority over capillary morphogenesis protein-2 based decoys as anthrax toxin inhibitors.

Abstract

Anthrax toxin is the major virulence factor produced by Bacillus anthracis. The toxin consists of three protein subunits: protective antigen (PA), lethal factor, and edema factor. Inhibition of PA binding to its receptors, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2) can effectively block anthrax intoxication, which is particularly valuable when the toxin has already been overproduced at the late stage of anthrax infection, thus rendering antibiotics ineffectual. Receptor-like agonists, such as the mammalian cell-expressed von Willebrand factor type A (vWA) domain of CMG2 (sCMG2), have demonstrated potency against the anthrax toxin. However, the soluble vWA domain of TEM8 (sTEM8) was ruled out as an anthrax toxin inhibitor candidate due to its inferior affinity to PA. In the present study, we report that L56A, a PA-binding-affinity-elevated mutant of sTEM8, could inhibit anthrax intoxication as effectively as sCMG2 in Fisher 344 rats. Additionally, pharmacokinetics showed that L56A and sTEM8 exhibit advantages over sCMG2 with better lung-targeting and longer plasma retention time, which may contribute to their enhanced protective ability in vivo. Our results suggest that receptor decoys based on TEM8 are promising anthrax toxin inhibitors and, together with the pharmacokinetic studies in this report, may contribute to the development of novel anthrax drugs.

• Authors: Chenguang Cai, Jinjing Che, Long Xu, Qiang Guo, Yirong Kong, Ling Fu, Junjie Xu, Yuanguo Cheng, Wei Chen
• Journal: PloS one (PLoS One) Vol. 6 Issue 6 Pg. e20646 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21674060 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Bacterial
• Antitoxins
• Bacterial Toxins
• Blood Proteins
• Receptors, Cell Surface
• Receptors, Peptide
• anthrax toxin

Topics

• Amino Acid Substitution
• Animals
• Antigens, Bacterial (metabolism)
• Antitoxins (chemistry, pharmacology)
• Bacterial Toxins (antagonists & inhibitors, metabolism)
• Blood Proteins (metabolism)
• Cell Line
• Kidney (drug effects, metabolism)
• Lung (drug effects, metabolism)
• Male
• Mice
• Mutation
• Rats
• Receptors, Cell Surface (chemistry, genetics)
• Receptors, Peptide (chemistry, genetics)
• Solubility
• Tissue Distribution