Quinolinol and peptide inhibitors of zinc protease in botulinum neurotoxin A: Effects of zinc ion and peptides on inhibition

Lai, Huiguo; Feng, Minghao; Roxas-Duncan, Virginia; Dakshanamurthy, Sivanesan; Smith, Leonard A.; Yang, David C.H.

doi:10.1016/j.abb.2009.09.008

Cited by 35 publications

(41 citation statements)

References 36 publications

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“…Quinolinol derivatives (QAQ, NSC1010 and others) were reported to inhibit BoNT/A as determined by biochemical, cell and tissue based assay [24]. Mechanism of QAQ binding to BoNT/A-LC and mode of inhibition was studied in detail by Lai et al [25]. Similarly, a high throughput screening of a library of hydroxamates [26] resulted in the selection of 4-dichlorocinnamic hydroxamate as a lead structure for further development [10].…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Quinolinol Inhibitor Identified Provides Protection against BoNT/A in Mice

Singh

Chaudhary

et al. 2012

PLoS ONE

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Botulinum neurotoxins (BoNTs), etiological agents of the life threatening neuroparalytic disease botulism, are the most toxic substances currently known. The potential for the use as bioweapon makes the development of small-molecule inhibitor against these deadly toxins is a top priority. Currently, there are no approved pharmacological treatments for BoNT intoxication. Although an effective vaccine/immunotherapy is available for immuno-prophylaxis but this cannot reverse the effects of toxin inside neurons. A small-molecule pharmacological intervention, especially one that would be effective against the light chain protease, would be highly desirable. Similarity search was carried out from ChemBridge and NSC libraries to the hit (7-(phenyl(8-quinolinylamino)methyl)-8-quinolinol; NSC 84096) to mine its analogs. Several hits obtained were screened for in silico inhibition using AutoDock 4.1 and 19 new molecules selected based on binding energy and Ki. Among these, eleven quinolinol derivatives potently inhibited in vitro endopeptidase activity of botulinum neurotoxin type A light chain (rBoNT/A-LC) on synaptosomes isolated from rat brain which simulate the in vivo system. Five of these inhibitor molecules exhibited IC50 values ranging from 3.0 nM to 10.0 µM. NSC 84087 is the most potent inhibitor reported so far, found to be a promising lead for therapeutic development, as it exhibits no toxicity, and is able to protect animals from pre and post challenge of botulinum neurotoxin type A (BoNT/A).

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Section: Introductionmentioning

confidence: 99%

Small-Molecule Quinolinol Inhibitor Identified Provides Protection against BoNT/A in Mice

Singh

Chaudhary

et al. 2012

PLoS ONE

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“…The quinoline-based compounds are known inhibitors of BoNT/A [38]. Lai et al reported that the 8-hydroxyquinol and derivatives showed non-competitive inhibition on BoNT/A [14]. C2 is a piperidine-based chemotype and also contains an interesting benzodioxol group.…”

Section: Resultsmentioning

confidence: 99%

Structural insight into exosite binding and discovery of novel exosite inhibitors of botulinum neurotoxin serotype A through in silico screening

Legler

Southall

et al. 2014

J Comput Aided Mol Des

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Botulinum neurotoxin serotype A (BoNT/A) is the most lethal toxin among the Tier 1 Select Agents. Development of potent and selective small molecule inhibitors against BoNT/A zinc metalloprotease remains a challenging problem due to its exceptionally large substrate binding surface and conformational plasticity. The exosites of the catalytic domain of BoNT/A are intriguing alternative sites for small molecule intervention, but their suitability for inhibitor design remains largely unexplored. In this study, we employed two recently identified exosite inhibitors, D-chicoric acid and lomofungin, to probe the structural features of the exosites and molecular mechanisms of synergistic inhibition. The results showed that D-chicoric acid favors binding at the α-exosite, whereas lomofungin preferentially binds at the β-exosite by mimicking the substrate β-sheet binding interaction. Molecular dynamics simulations and binding interaction analysis of the exosite inhibitors with BoNT/A revealed key elements and hot-spots that likely contribute to the inhibitor binding and synergistic inhibition. Finally, we performed database virtual screening for novel inhibitors of BoNT/A targeting the exosites. Hits C1 and C2 showed non-competitive inhibition and likely target the α- and β-exosites, respectively. The identified exosite inhibitors may provide novel candidates for structure-based development of therapeutics against BoNT/A intoxication.

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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%

“…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. 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%

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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Quinolinol and peptide inhibitors of zinc protease in botulinum neurotoxin A: Effects of zinc ion and peptides on inhibition

Cited by 35 publications

References 36 publications

Small-Molecule Quinolinol Inhibitor Identified Provides Protection against BoNT/A in Mice

Small-Molecule Quinolinol Inhibitor Identified Provides Protection against BoNT/A in Mice

Structural insight into exosite binding and discovery of novel exosite inhibitors of botulinum neurotoxin serotype A through in silico screening

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

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