ArticleAntimicrobial agents and chemotherapy2005
Protection from anthrax toxin-mediated killing of macrophages by the combined effects of furin inhibitors and chloroquine.
Article in Antimicrobial agents and chemotherapy, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 38 citations in OpenAlex.
- FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice.Arteriosclerosis, thrombosis, and vascular biology · 2019Article
- Furin inhibitor D6R suppresses epithelial-mesenchymal transition in SW1990 and PaTu8988 cells via the Hippo-YAP signaling pathway.Oncology letters · 2018Article
- Association of Rs2071410 on Furin with Transient Ischemic Attack Susceptibility and Prognosis in a Chinese Population.Medical science monitor : international medical journal of experimental and clinical research · 2016Article
- Inhibitors of the Metalloproteinase Anthrax Lethal Factor.Current topics in medicinal chemistry · 2016Review
- Identification of potent and compartment-selective small molecule furin inhibitors using cell-based assays.Biochemical pharmacology · 2015Article
- An overview of investigational toxin-directed therapies for the adjunctive management of Bacillus anthracis infection and sepsis.Expert opinion on investigational drugs · 2015Review
- Chloroquine-containing compounds: a patent review (2010 - 2014).Expert opinion on therapeutic patents · 2015Review
- Small molecule inhibitors of Bacillus anthracis protective antigen proteolytic activation and oligomerization.Journal of medicinal chemistry · 2012Article
- The biology and therapeutic targeting of the proprotein convertases.Nature reviews. Drug discovery · 2012Review
- Binding and cell intoxication studies of anthrax lethal toxin.Molecular biology reports · 2012Article
- Domain flexibility modulates the heterogeneous assembly mechanism of anthrax toxin protective antigen.Journal of molecular biology · 2012Article
- Associations between genetic variations in the FURIN gene and hypertension.BMC medical genetics · 2010Article
- Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules.The Journal of biological chemistry · 2009Article
- A dual-purpose protein ligand for effective therapy and sensitive diagnosis of anthrax.The protein journal · 2008Article
- Amiodarone and bepridil inhibit anthrax toxin entry into host cells.Antimicrobial agents and chemotherapy · 2007Article
- Synthetic small molecule furin inhibitors derived from 2,5-dideoxystreptamine.Proceedings of the National Academy of Sciences of the United States of America · 2006Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Cell surface proteolytic processing of anthrax protective antigen by furin or other furin-related proteases is required for its oligomerization, endocytosis, and function as a translocon for anthrax lethal and edema factors. Countering toxin lethality is essential to developing effective chemotherapies for anthrax infections that have proceeded beyond the stage at which antibiotics are effective. The primary target for toxin is the macrophage, which can be killed by lethal factor via both necrotic and apoptotic pathways. Here we show that three high-affinity inhibitors of furin efficiently blocked killing of murine J774A.1 macrophages by recombinant protective antigen plus lethal factor: RRD-eglin and RRDG-eglin, developed by engineering the protein protease inhibitor eglin c, and the peptide boronic acid inhibitor acetyl-Arg-Glu-Lys-boroArg pinanediol. Inhibition of killing was dose dependent and correlated with prevention of protective antigen processing. Previous studies have shown that weak bases, such as chloroquine, which neutralize acidic compartments, also interfere with toxin-dependent killing. Here we show that combining furin inhibitors and chloroquine strongly augments the inhibition of toxin-dependent killing, suggesting that combined use of antifurin drugs and chloroquine might provide enhanced therapeutic benefits. Reversible furin inhibitors protected against anthrax toxin killing for at least 5 h, but by 8 h, toxin-dependent killing resumed even though furin inhibitors were still active. An irreversible chloromethylketone inhibitor did not exhibit this loss of protection.
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