ArticleInfection and immunity2009
Investigation of new dominant-negative inhibitors of anthrax protective antigen mutants for use in therapy and vaccination.
Article in Infection and immunity, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 13 citations in OpenAlex.
- Exotoxin-Targeted Drug Modalities as Antibiotic Alternatives.ACS infectious diseases · 2022Review
- Inhibition of Pore-Forming Proteins.Toxins · 2019Review
- An overview of investigational toxin-directed therapies for the adjunctive management of Bacillus anthracis infection and sepsis.Expert opinion on investigational drugs · 2015Review
- Review
- Designing inhibitors of anthrax toxin.Expert opinion on drug discovery · 2014Review
- A human/murine chimeric fab antibody neutralizes anthrax lethal toxin in vitro.Clinical & developmental immunology · 2013Article
- Obstructing toxin pathways by targeted pore blockage.Chemical reviews · 2012Review
- A chimeric protein that functions as both an anthrax dual-target antitoxin and a trivalent vaccine.Antimicrobial agents and chemotherapy · 2010Article
- Residue histidine 669 is essential for the catalytic activity of Bacillus anthracis lethal factor.Journal of bacteriology · 2010Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The lethal toxin (LeTx) of Bacillus anthracis plays a key role in the pathogenesis of anthrax. The protective antigen (PA) is a primary part of the anthrax toxin and forms LeTx by combination with lethal factor (LF). Phenylalanine-427 (F427) is crucial for PA function. This study was designed to discover potential novel therapeutic agents and vaccines for anthrax. This was done by screening PA mutants that were mutated at the F427 residue for a dominant-negative inhibitory (DNI) phenotype which was nontoxic but inhibited the toxicity of the wild-type LeTx. For this, PA residue F427 was first mutated to each of the other 19 naturally occurring amino acids. The cytotoxicity and DNI phenotypes of the mutated PA proteins were tested in the presence of 1 microg/ml LF in RAW264.7 cells and were shown to be dependent on the individual amino acid replacements. A total of 16 nontoxic mutants with various levels of DNI activity were identified in vitro. Among them, F427D and F427N mutants had the highest DNI activities in RAW264.7 cells. Both mutants inhibited LeTx intoxication in mice in a dose-dependent way. Furthermore, they induced a Th2-predominant immune response and protected mice against a challenge with five 50% lethal doses of LeTx. The protection was correlated mainly with a low level of interleukin-1 beta (IL-1 beta) and with high levels of PA-specific immunoglobulin G1, IL-6, and tumor necrosis factor alpha. Thus, PA DNI mutants, such as F427D and F427N mutants, may serve in the development of novel therapeutic agents and vaccines to fight B. anthracis infections.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.