Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity

Burnett, James C.; Schmidt, James J.; Stafford, Robert G.; Panchal, Rekha G.; Nguyen, Tam Luong; Hermone, Ann; Vennerstrom, Jonathan L.; McGrath, Connor F.; Lane, Douglas; Sausville, Edward A.; Zaharevitz, Daniel; Gussio, Rick; Bavari, Sina

doi:10.1016/j.bbrc.2003.08.112

Cited by 94 publications

(154 citation statements)

References 35 publications

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“…[31][32][33] This intermolecular hydrogen bond is also consistent with our docked model of mpp-RATKML, 33 in which the Arg side chain guanidinium is predicted to engage in a hydrogen bond with the Glu 163 side chain carboxylate.…”

Section: Molecular Docking Of Smnpis 1-4 Demonstrates a Consistency Wsupporting

confidence: 82%

“…Compounds 1-4 were docked in the BoNT/A LC substrate binding cleft to determine if they would also engage in intermolecular contacts that were comparable to those predicted for other structurally diverse SMNPIs. [31][32][33] Similar to our previously docked models of ACQ inhibitors, 31,32 the 7-chloro substituents of 1-3 ( Figure 3A-C) and one of the ACQs of 4 ( Figure 4A and B) engage in favorable hydrophobic contacts with residues Phe 162, Phe 163, and Thr 219 of hydrophobic binding subsite 1 [31][32][33] (also described as the S1′ binding site 34 ). At the same time, the quinoline nitrogens of the inhibitors are positioned so that this heteroatom may interfere with the enzyme's catalytic engine.…”

Section: Molecular Docking Of Smnpis 1-4 Demonstrates a Consistency Wsupporting

confidence: 75%

“…31 Further supporting this approach are the findings of Deshpande et al 35 and Sheridan et al, 36 demonstrating that ACQ-based drugs, which also possess a separate ionizable nitrogen atom (e.g., amodiaquine), delay BoNT/A induced muscle paralysis. In those studies, it was hypothesized that the compounds act by interfering with toxin translocation, most likely by increasing the pH of the toxin-mediated endosome.…”

Section: Resultsmentioning

confidence: 84%

“…31 Additionally, we proposed binding modes for the compounds and developed a common pharmacophore for BoNT/A LC inhibition. 31 In a subsequent molecular dynamics study, we demonstrated that conformationally flexible loops surrounding the BoNT/A LC substrate binding cleft may reorient to decrease the solvent accessibility of the cleft (as compared to respective energy refined structures), while simultaneously providing more hydropathically feasible binding contacts for SMNPIs. 32 The molecular dynamics studies were pivotal for identifying a binding mode 33 for the potent pseudo-peptide inhibitor 2-mercapto-3-phenylpropionyl-RATKML (mpp-RAT-KML, K i ) 330 nM 34 ).…”

Section: Introductionmentioning

confidence: 99%

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A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

et al. 2007

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We previously identified structurally diverse small molecule (non-peptidic) inhibitors (SMNPIs) of the botulinum neurotoxin serotype A (BoNT/A) light chain (LC). Of these, several (including antimalarial drugs) contained a 4-amino-7-chloroquinoline (ACQ) substructure and a separate positive ionizable amine component. The same antimalarials have also been found to interfere with BoNT/A translocation into neurons, via pH elevation of the toxin-mediated endosome. Thus, this structural class of small molecules may serve as dualfunction BoNT/A inhibitors. In this study, we used a refined pharmacophore for BoNT/A LC inhibition to identify four new, potent inhibitors of this structural class (IC 50 's ranged from 3.2 to 17 µM). Molecular docking indicated that the binding modes for the new SMNPIs are consistent with those of other inhibitors that we have identified, further supporting our structure-based pharmacophore. Finally, structural motifs of the new SMNPIs, as well as two structure-based derivatives, were examined for activity, providing valuable information about pharmacophore component contributions to inhibition.

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Section: Molecular Docking Of Smnpis 1-4 Demonstrates a Consistency Wsupporting

confidence: 82%

Section: Molecular Docking Of Smnpis 1-4 Demonstrates a Consistency Wsupporting

confidence: 75%

Section: Resultsmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

et al. 2007

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“…The design and synthesis of dimeric analogs of CQ that exploit the thermodynamic advantages imparted by polyvalency (11,12) has been previously studied in the context of malaria (13)(14)(15). The synthesis of heteroalkane-bridged bisquinolines did not produce sufficient antimalarial activity to warrant further investigation (14).…”

mentioning

confidence: 99%

Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

McAfee¹,

Zhang²,

Samanta³

et al. 2012

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

357

313

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Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer.cell death | stress responses | cancer cell survival | drug resistance | antimalarials A utophagy, the sequestration of organelles and proteins in autophagic vesicles (AVs) and degradation of this cargo through lysosomal fusion (1), allows tumor cells to survive metabolic and therapeutic stresses (2-5). Therapy-induced autophagy is a key resistance mechanism to many anticancer agents (6), and autophagy levels are increased in most cancers (7). Chloroquine (CQ; Fig. 1, compound 1) derivatives block autophagy by impairing lysosomal function (3,8,9). Studies in multiple mouse models of malignancy have demonstrated that autophagy inhibition with CQ derivatives augments the efficacy of a variety of anticancer agents. Clinical trials combining cancer therapies with hydroxychloroquine (HCQ; Fig. 1), have been launched, and preliminary results indicate these combinations have activity (6). However, pharmacokinetic (PK)-pharmacodynamic (PD) studies conducted in patients receiving HCQ for cancer therapy have indicated that the high micromolar concentrations of HCQ required to inhibit autophagy in vitro are inconsistently achieved in humans (10). There is an unmet need to develop more potent inhibitors of autophagy.The design and synthesis of dimeric analogs of CQ that exploit the thermodynamic advantages imparted by polyvalency (11, 12) has been previously studied in the context of malaria (13-15). The synthesis of heteroalkane-bridged bisquinolines did not produce sufficient antimalarial activity to warrant further investigation (14). Subsequently, a seri...

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Botulinum Toxin (Clostridium Botulinum)

Pilch¹,

Bray²

2011

Encyclopedia of Bioterrorism Defense

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Botulinum toxin is classified as a Category A agent of bioterrorism because of the ability of an extremely small dose to interrupt cholinergic nerve transmission, leading to paralysis and death. Treatment is currently limited to the carefully supervised administration of equine antitoxin after early symptom onset, an approach that would be inadequate in the event of a massive botulism outbreak. Efforts to develop new therapies applicable to a mass‐casualty situation focus on blocking specific steps in pathogenesis and speeding the recovery of neuronal and muscular function. This entry first reviews basic features of botulinum toxin, sources of poisoning, the clinical syndrome, current approaches to diagnosis and management, and the potential of the toxin as a bioterrorist weapon. It then presents the steps in the pathogenesis and recovery from botulism at the molecular level, accompanied by a description of current research efforts aimed at developing specific therapeutic measures.

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Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity

Cited by 94 publications

References 35 publications

A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency

Botulinum Toxin (Clostridium Botulinum)

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