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Scientists design potent anthrax toxin inhibitor
April 25, 2006Technique may also be applicable to other disease toxins
Scientists funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), have engineered a powerful inhibitor of anthrax toxin that worked well in small-scale animal tests.
"This novel approach to the design of anthrax antitoxin is an important advance, not only for the value it may have in anthrax treatment, but also because this technique could be used to design better therapies for cholera and other diseases," says NIH Director Elias A. Zerhouni, M.D.
The research appears in the April 23 online edition of the journal Nature Biotechnology.
Led by NIAID grantees Ravi S. Kane, Ph.D., of Rensselaer Polytechnic Institute, in Troy, NY, and Jeremy Mogridge, Ph.D., of the University of Toronto, the investigators built a fatty bubble studded with small proteins that can cling tightly to the cell membrane receptor-binding protein used by anthrax toxin to gain entry into a host cell.
The protein-spiked fatty bubble, or "functionalized liposome," hampers a critical early step in the assembly process that anthrax toxin must undergo to become fully active. In test-tube experiments, the inhibitor, which is covered with multiple short proteins (peptides), was 10,000 times more potent than unattached peptides.
"If the effectiveness of anthrax inhibitors designed in this fashion is confirmed by additional testing, they could one day be important adjuncts to standard antibiotic therapy for the treatment of inhalation anthrax," says NIAID Director Anthony S. Fauci, M.D.
The spore-forming bacterium Bacillus anthracis produces a toxin that causes anthrax symptoms. Antibiotics are used to treat anthrax, but even with such therapy, inhalation anthrax, the most severe form of the disease, has a fatality rate of 75 percent.
"There would be real value to having an additional form of therapy available to physicians confronting a case of inhalation anthrax," notes Phillip J. Baker, Ph.D., anthrax program officer at NIAID.
Anthrax toxin has three parts: protective antigen (PA), a protein that binds to a receptor on the target cell surface; and two enzymes that must be transported into the cell to cause damage. The enzymatic portions of the toxin enter the cell through a pore created for them by PA after it binds to the cell's outer surface. PA can be seen as a bundle of seven cigar-shaped parts, a molecular arrangement referred to as "polyvalent," meaning it displays multiple binding sites.
The inhibitor designed by Dr. Kane and his colleagues is also polyvalent. Just as a glove matches the shape of a hand more closely than a mitten, and so fits more snugly, the polyvalent inhibitor binds the toxin at multiple sites and is orders of magnitude more potent than an inhibitor that binds at a single site. The multiple peptides on the functionalized liposome are arranged with the same average spacing as the binding sites of the PA molecule, which permits a firmer bond between the two, explains Dr. Kane. When the inhibitor is bound tightly to PA, the subsequent steps of enzyme entry cannot occur and the toxin is effectively neutralized.
The investigators tested the anthrax inhibitor in rats. When given in relatively small doses, injection of the inhibitor at the same time as anthrax toxin prevented five out of nine rats from becoming ill. Slightly higher doses of the inhibitor prevented eight out of nine rats from being sickened by anthrax toxin. Nine additional rats were injected with anthrax toxin only. Of these, eight became gravely ill. This experiment was the first to show the efficacy of a liposome-based polyvalent inhibitor in animals, says Dr. Kane.
Dr. Kane says the recent experiments demonstrate a proof of principle and suggest that polyvalent inhibitors could be used along with antibiotics in a clinical setting. Aside from its inherent toxicity, anthrax toxin also accelerates the disease process. Thus, combining antibiotics with a toxin inhibitor might act synergistically to lessen or halt anthrax symptoms, notes Dr. Kane.
Using the same technique of placing multiple peptides on a liposome, the researchers also created a polyvalent inhibitor of cholera toxin that functioned well in test-tube experiments.
In the next phase of their research, Drs. Kane and Mogridge and their colleagues plan to test the action of their inhibitor in animals after infecting them with B. anthracis and allowing the disease process to begin. They also will evaluate the inhibitor with and without adjunct antibiotic therapy.
NIH/National Institute of Allergy and Infectious Diseases
Led by NIAID grantees Ravi S. Kane, Ph.D., of Rensselaer Polytechnic Institute, in Troy, NY, and Jeremy Mogridge, Ph.D., of the University of Toronto, the investigators built a fatty bubble studded with small proteins that can cling tightly to the cell membrane receptor-binding protein used by anthrax toxin to gain entry into a host cell.
The protein-spiked fatty bubble, or "functionalized liposome," hampers a critical early step in the assembly process that anthrax toxin must undergo to become fully active. In test-tube experiments, the inhibitor, which is covered with multiple short proteins (peptides), was 10,000 times more potent than unattached peptides.
"If the effectiveness of anthrax inhibitors designed in this fashion is confirmed by additional testing, they could one day be important adjuncts to standard antibiotic therapy for the treatment of inhalation anthrax," says NIAID Director Anthony S. Fauci, M.D.
The spore-forming bacterium Bacillus anthracis produces a toxin that causes anthrax symptoms. Antibiotics are used to treat anthrax, but even with such therapy, inhalation anthrax, the most severe form of the disease, has a fatality rate of 75 percent.
"There would be real value to having an additional form of therapy available to physicians confronting a case of inhalation anthrax," notes Phillip J. Baker, Ph.D., anthrax program officer at NIAID.
Anthrax toxin has three parts: protective antigen (PA), a protein that binds to a receptor on the target cell surface; and two enzymes that must be transported into the cell to cause damage. The enzymatic portions of the toxin enter the cell through a pore created for them by PA after it binds to the cell's outer surface. PA can be seen as a bundle of seven cigar-shaped parts, a molecular arrangement referred to as "polyvalent," meaning it displays multiple binding sites.
The inhibitor designed by Dr. Kane and his colleagues is also polyvalent. Just as a glove matches the shape of a hand more closely than a mitten, and so fits more snugly, the polyvalent inhibitor binds the toxin at multiple sites and is orders of magnitude more potent than an inhibitor that binds at a single site. The multiple peptides on the functionalized liposome are arranged with the same average spacing as the binding sites of the PA molecule, which permits a firmer bond between the two, explains Dr. Kane. When the inhibitor is bound tightly to PA, the subsequent steps of enzyme entry cannot occur and the toxin is effectively neutralized.
The investigators tested the anthrax inhibitor in rats. When given in relatively small doses, injection of the inhibitor at the same time as anthrax toxin prevented five out of nine rats from becoming ill. Slightly higher doses of the inhibitor prevented eight out of nine rats from being sickened by anthrax toxin. Nine additional rats were injected with anthrax toxin only. Of these, eight became gravely ill. This experiment was the first to show the efficacy of a liposome-based polyvalent inhibitor in animals, says Dr. Kane.
Dr. Kane says the recent experiments demonstrate a proof of principle and suggest that polyvalent inhibitors could be used along with antibiotics in a clinical setting. Aside from its inherent toxicity, anthrax toxin also accelerates the disease process. Thus, combining antibiotics with a toxin inhibitor might act synergistically to lessen or halt anthrax symptoms, notes Dr. Kane.
Using the same technique of placing multiple peptides on a liposome, the researchers also created a polyvalent inhibitor of cholera toxin that functioned well in test-tube experiments.
In the next phase of their research, Drs. Kane and Mogridge and their colleagues plan to test the action of their inhibitor in animals after infecting them with B. anthracis and allowing the disease process to begin. They also will evaluate the inhibitor with and without adjunct antibiotic therapy.
NIH/National Institute of Allergy and Infectious Diseases
Anthrax Toxin Current Events and Anthrax Toxin News RSSProtein data bank archives 50,000th molecule structure
The Protein Data Bank (PDB) based at Rutgers, The State University of New Jersey, and the University of California-San Diego (UCSD) this month reached a significant milestone in its 37-year history. The 50,000th molecule structure was released into its archive, joining other structures vital to pharmacology, bioinformatics and education.
How do infections and toxins launch a cell's self-destruct and alarm system?
Cells are coded with several programs for self-destruction. Many cells die peacefully. Others cause a ruckus on their way out.
Using carbon nanotubes to seek and destroy anthrax toxin and other harmful proteins
Researchers at Rensselaer Polytechnic Institute have developed a new way to seek out specific proteins, including dangerous proteins such as anthrax toxin, and render them harmless using nothing but light.
Scripps research scientists develop innovative dual action anthrax vaccine-antitoxin combination
The immune response generated in rats by the new agent protects against lethal toxin exposure after only one injection, and is faster and stronger than any currently available vaccine.
Cheaper, potentially better disease treatments expected from faster approach to developing therapeutic antibodies
A method of mass-producing disease-fighting antibodies entirely within bacteria has been developed by a research group at The University of Texas at Austin.
New anthrax inhibitor could combat antibiotic-resistant strains
In a new approach to treating anthrax exposure, a team of scientists has created an inhibitor designed to tackle the growing threat of antibiotic-resistant strains.
Basic work on E. coli identifies two new keys to regulation of bacterial gene expression
The cellular process of transcription, in which the enzyme RNA polymerase constructs chains of RNA from information contained in DNA, depends upon previously underappreciated sections of both the DNA promoter region and RNA polymerase, according to work done with the bacterium E. coli.
Anthrax inhibitor counteracts toxin, may lead to new therapeutics
Researchers from Rensselaer Polytechnic Institute and the University of Toronto have designed a nanoscale assembly of molecules that successfully counteracts and inhibits anthrax toxin in animal and laboratory experiments.
New antibody shows promise as cure for anthrax
A new anthrax antibody engineered by scientists at The University of Texas at Austin protects and defends against inhalation anthrax without the use of antibiotics and other more expensive antibodies.
Unexpected features of anthrax toxin may lead to new types of therapies
Surprising new insights about the acid pH levels required for anthrax toxin to invade the cells of the body may help accelerate development of medications for the treatment of anthrax, a disease caused by a spore-forming bacterium.
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