Identification of Clinically Viable Quinolinol Inhibitors of Botulinum Neurotoxin A Light Chain

Caglič, Dejan; Krutein, Michelle C.; Bompiani, Kristin M.; Barlow, Deborah; Benoni, Galit; Pelletier, Jeffrey C.; Reitz, Allen B.; Lairson, Luke L.; Houseknecht, Karen L.; Smith, Garry R.; Dickerson, Tobin J.

doi:10.1021/jm4012164

Cited by 43 publications

(53 citation statements)

References 27 publications

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“…compound 15 (NSC84094). 28–30 The quinolinol core structure is present in the FDA-approved antibiotic chloroxine 37 as well as in the experimental drug PBT2, which has been tested in clinical trials as a therapy for Alzheimer’s disease. 38 A distinct advantage that quinolinols possess over more traditional zinc-chelating hydroxamates is increased lipophilicity that enhances their ability to penetrate cell membranes, which in effect would increase a molecule’s ability to inhibit the intracellular BoNT/A LC.…”

Section: Introductionmentioning

confidence: 99%

“…29, 30 Previously, the structure-activity relationship (SAR) of the 7-position on the quinolinol ring was explored extensively via screening of a Betti reaction library (Figure 1). 28 We hypothesized that functionalization at alternative positions on the quinolinol ring could also be fruitful for the discovery of new and possibly more potent BoNT/A inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Newly Designed Quinolinol Inhibitors Mitigate the Effects of Botulinum Neurotoxin A in Enzymatic, Cell-Based, and ex Vivo Assays

et al. 2017

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Botulinum neurotoxin A (BoNT/A) is one of the most deadly toxins, and is the etiological agent of the potentially fatal condition, botulism. Herein, we investigated 8-hydroxyquinoline (quinolin-8-ol) as a potential inhibitor scaffold for preventing the deadly neurochemical effects of the toxin. Quinolinols are known chelators that can disrupt the BoNT/A metalloprotease zinc-containing active site, thus impeding its proteolysis of the endogenous protein substrate, synaptosomal-associated protein 25 (SNAP-25). Using this information, the structure-activity relationship (SAR) of the quinolinol-5-sulfonamide scaffold was explored through preparation of a crude sulfonamide library, and evaluating the library in a BoNT/A LC enzymatic assay. Potency optimization of the sulfonamide hit compounds was undertaken as informed by docking studies, granting a lead compound with a submicromolar Ki. These quinolinol analogues demonstrated inhibitory activity in a cell-based model for SNAP-25 cleavage and an ex vivo assay for BoNT/A-mediated muscle paralysis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Newly Designed Quinolinol Inhibitors Mitigate the Effects of Botulinum Neurotoxin A in Enzymatic, Cell-Based, and ex Vivo Assays

et al. 2017

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“…A number of laboratories have focused on identifying small molecule inhibitors that block BoNT catalytic activity with high specificity and high affinity [85–89]. These approaches rely on good high-throughput screening approaches to identify lead compounds that can then be further screened using additional in vitro and cell-based assays, followed by in vivo animal studies.…”

Section: Current Antitoxins Against Botulismmentioning

confidence: 99%

Cargo-Delivery Platforms for Targeted Delivery of Inhibitor Cargos Against Botulism

Wilson¹,

Ho²

2014

CTMC

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Delivering therapeutic cargos to specific cell types in vivo poses many technical challenges. There is currently a plethora of drug leads and therapies against numerous diseases, ranging from small molecule compounds to nucleic acids to peptides to proteins with varying binding or enzymatic functions. Many of these candidate therapies have documented potential for mitigating or reversing disease symptoms, if only a means for gaining access to the intracellular target were available. Recent advances in our understanding of the biology of cellular uptake and transport processes and the mode of action of bacterial protein toxins have accelerated the development of toxin-based cargo-delivery vehicle platforms. This review provides an updated survey of the status of available platforms for targeted delivery of therapeutic cargos, outlining various strategies that have been used to deliver different types of cargo into cells. Particular emphasis is placed on the application of toxin-based approaches, examining critical issues that have hampered realization of post-intoxication antitoxins against botulism.

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“…The most common inhibition strategy has been to employ zinc chelator groups such as hydroxamates 22–23 and quinolinols 24–27 or SNAP-25 peptidomimetics 28–30 with the goal of competing with SNAP-25 for the BoNT/A LC active site. Disruption of SNAP-25 binding at the LC exosites with small-molecule inhibitors has also been explored.…”

Section: Introductionmentioning

confidence: 99%

Metal Ions Effectively Ablate the Action of Botulinum Neurotoxin A

et al. 2017

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Botulinum neurotoxin serotype A (BoNT/A) causes a debilitating and potentially fatal illness known as botulism. The toxin is also a bioterrorism threat, yet no pharmacological antagonist to counteract its effects has reached clinical approval. Existing strategies to negate BoNT/A intoxication have looked to antibodies, peptides or organic small molecules as potential therapeutics. In this work, a departure from the traditional drug discovery mindset was pursued, in which the enzyme’s susceptibility to metal ions was exploited. A screen of a series of metal salts showed marked inhibitory activity of group 11 and 12 metals against the BoNT/A light chain (LC) protease. Enzyme kinetics revealed that copper (I) and (II) cations displayed noncompetitive inhibition of the LC (Ki ≈ 1 μM), while mercury (II) cations were 10-fold more potent. Crystallographic and mutagenesis studies elucidated a key binding interaction between Cys165 on BoNT/A LC and the inhibitory metals. As potential copper prodrugs, ligand-copper complexes were examined in a cell-based model and were found to prevent BoNT/A cleavage of the endogenous protein substrate, SNAP-25, even at low μM concentrations of complexes. Further investigation of the complexes suggested a bioreductive mechanism causing intracellular release of copper, which directly inhibited the BoNT/A protease. In vivo experiments demonstrated that copper (II) dithiocarbamate and bis(thiosemicarbazone) complexes could delay BoNT/A-mediated lethality in a rodent model, indicating their potential for treating the harmful effects of BoNT/A intoxication. Our studies illustrate that metals can be therapeutically viable enzyme inhibitors; moreover, enzymes that share homology with BoNT LCs may be similarly targeted with metals.

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Identification of Clinically Viable Quinolinol Inhibitors of Botulinum Neurotoxin A Light Chain

Cited by 43 publications

References 27 publications

Newly Designed Quinolinol Inhibitors Mitigate the Effects of Botulinum Neurotoxin A in Enzymatic, Cell-Based, and ex Vivo Assays

Newly Designed Quinolinol Inhibitors Mitigate the Effects of Botulinum Neurotoxin A in Enzymatic, Cell-Based, and ex Vivo Assays

Cargo-Delivery Platforms for Targeted Delivery of Inhibitor Cargos Against Botulism

Metal Ions Effectively Ablate the Action of Botulinum Neurotoxin A

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