Cross-inhibition between furin and lethal factor inhibitors

Peinado, Juan R.; Kacprzak, Magdalena M.; Leppla, Stephen H.; Lindberg, Iris

doi:10.1016/j.bbrc.2004.07.012

Cited by 33 publications

(33 citation statements)

References 18 publications

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“…This is in accord with recent studies showing that oligo-Darginine-based furin inhibitors provide protection against anthrax toxin lethality (34,38). Furthermore, we have shown that the combination of furin family inhibitors with the weak base chloroquine substantially augmented protection from toxin lethality.…”

Section: Discussionsupporting

confidence: 92%

Protection from Anthrax Toxin-Mediated Killing of Macrophages by the Combined Effects of Furin Inhibitors and Chloroquine

Komiyama¹,

Swanson

Fuller³

2005

Antimicrob Agents Chemother

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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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Section: Discussionsupporting

confidence: 92%

Protection from Anthrax Toxin-Mediated Killing of Macrophages by the Combined Effects of Furin Inhibitors and Chloroquine

Komiyama¹,

Swanson

Fuller³

2005

Antimicrob Agents Chemother

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“…Furin inhibitors that prevent the activation of bacterial toxins, such as anthrax toxin (40), are under development. Results from mice protected against anthrax toxemia by systemic treatment with furin inhibitors suggest that topical application might have acceptable side effects (41).…”

Section: Discussionmentioning

confidence: 99%

Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection

Richards

Lowy

Schiller

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

302

325

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Papillomaviruses (PV) comprise a large family of nonenveloped DNA viruses that include the oncogenic PV types that are the causative agents of human cervical cancer. As is true of many animal DNA viruses, PV are taken into the cell by endocytosis and must escape from the endosomal compartment to the cytoplasm to initiate infection. Here we show that this step depends on the site-specific enzymatic cleavage of the PV minor virion protein L2 at a consensus furin recognition site. Cleavage by furin, a cellencoded proprotein convertase, is known to be required for endosome escape by many bacterial toxins. However, to our knowledge, furin has not been previously implicated in the viral entry process. This step is potentially a target for PV inhibition.proprotein convertase

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“…Because cell surface-associated PCs in bronchial epithelial cells are the first to encounter inhaled pathogens, including influenza A H5N1 (bird flu), we developed an inhaled, nanoparticle-immobilized drug to minimize potential side-effects and optimize delivery. The specific furin inhibitors we designed are superior relative to D-Arg-peptides, which have been shown to cross-react with multiple host and pathogen targets, including both furin and anthrax lethal factor (6).…”

Section: Discussionmentioning

confidence: 99%

Targeting Host Cell Furin Proprotein Convertases as a Therapeutic Strategy against Bacterial Toxins and Viral Pathogens

Shiryaev

Remacle

Ratnikov

et al. 2007

Journal of Biological Chemistry

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Pathogens or their toxins, including influenza virus, Pseudomonas, and anthrax toxins, require processing by host proprotein convertases (PCs) to enter host cells and to cause disease. Conversely, inhibiting PCs is likely to protect host cells from multiple furin-dependent, but otherwise unrelated, pathogens. To determine if this concept is correct, we designed specific nanomolar inhibitors of PCs modeled from the extended cleavage motif TPQRERRRKKR2GL of the avian influenza H5N1 hemagglutinin. We then confirmed the efficacy of the inhibitory peptides in vitro against the fluorescent peptide, anthrax protective antigen (PA83), and influenza hemagglutinin substrates and also in mice in vivo against two unrelated toxins, anthrax and Pseudomonas exotoxin. Peptides with Phe/Tyr at P1 were more selective for furin. Peptides with P1 Thr were potent against multiple PCs. Our strategy of basing the peptide sequence on a furin cleavage motif known for an avian flu virus shows the power of starting inhibitor design with a known substrate. Our results confirm that inhibiting furin-like PCs protects the host from the distinct furin-dependent infections and lay a foundation for novel, host cell-focused therapies against acute diseases.

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Cross-inhibition between furin and lethal factor inhibitors

Cited by 33 publications

References 18 publications

Protection from Anthrax Toxin-Mediated Killing of Macrophages by the Combined Effects of Furin Inhibitors and Chloroquine

Protection from Anthrax Toxin-Mediated Killing of Macrophages by the Combined Effects of Furin Inhibitors and Chloroquine

Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection

Targeting Host Cell Furin Proprotein Convertases as a Therapeutic Strategy against Bacterial Toxins and Viral Pathogens

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