ArticleBiomacromolecules2011
Structure-based design of a heptavalent anthrax toxin inhibitor.
Article in Biomacromolecules, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 43 citations in OpenAlex.
- Click Chemistry as an Efficient Toolbox for Coupling Sterically Hindered Molecular Systems to Obtain Advanced Materials for Nanomedicine.International journal of molecular sciences · 2024Review
- Discovery of Stable and Selective Antibody Mimetics from Combinatorial Libraries of Polyvalent, Loop-Functionalized Peptoid Nanosheets.ACS nano · 2020Article
- Inhibition of Pore-Forming Proteins.Toxins · 2019Review
- Sortase-click strategy for defined protein conjugation on a heptavalent cyclodextrin scaffold.PloS one · 2019Article
- Dynamic Control of the Self-Assembling Properties of Cyclodextrins by the Interplay of Aromatic and Host-Guest Interactions.Frontiers in chemistry · 2019Article
- Synthesis of multivalent polymer-aptamer conjugates with enhanced inhibitory potency.International journal of nanomedicine · 2018Article
- Beyond Antibiotics: New Therapeutic Approaches for Bacterial Infections.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2016Article
- An overview of investigational toxin-directed therapies for the adjunctive management of Bacillus anthracis infection and sepsis.Expert opinion on investigational drugs · 2015Review
- Design of monodisperse and well-defined polypeptide-based polyvalent inhibitors of anthrax toxin.Angewandte Chemie (International ed. in English) · 2014Article
- Cationic PAMAM dendrimers as pore-blocking binary toxin inhibitors.Biomacromolecules · 2014Article
- Designing inhibitors of anthrax toxin.Expert opinion on drug discovery · 2014Review
- Cyclodextrin derivatives as anti-infectives.Current opinion in pharmacology · 2013Review
- Obstructing toxin pathways by targeted pore blockage.Chemical reviews · 2012Review
- Small molecule inhibitors of Bacillus anthracis protective antigen proteolytic activation and oligomerization.Journal of medicinal chemistry · 2012Article
- Review
- Manipulation of kinase signaling by bacterial pathogens.The Journal of cell biology · 2011Review
- Multivalent Inhibitors of Channel-Forming Bacterial Toxins.Current topics in microbiology and immunologyReview
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
The design of polyvalent molecules, consisting of multiple copies of a biospecific ligand attached to a suitable scaffold, represents a promising approach to inhibit pathogens and oligomeric microbial toxins. Despite the increasing interest in structure-based drug design, few polyvalent inhibitors based on this approach have shown efficacy in vivo. Here we demonstrate the structure-based design of potent biospecific heptavalent inhibitors of anthrax lethal toxin. Specifically, we illustrate the ability to design potent polyvalent ligands by matching the pattern of binding sites on the biological target. We used a combination of experimental studies based on mutagenesis and computational docking studies to identify the binding site for an inhibitory peptide on the heptameric subunit of anthrax toxin. We developed an approach based on copper-catalyzed azide-alkyne cycloaddition (click-chemistry) to facilitate the attachment of seven copies of the inhibitory peptide to a β-cyclodextrin core via a polyethylene glycol linker of an appropriate length. The resulting heptavalent inhibitors neutralized anthrax lethal toxin both in vitro and in vivo and showed appreciable stability in serum. Given the inherent biocompatibility of cyclodextrin and polyethylene glycol, these potent well-defined heptavalent inhibitors show considerable promise as anthrax antitoxins.
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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.