A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A

Harrell, William A.; Vieira, Rebecca C.; Ensel, Susan M.; Montgomery, Vicki A.; Guernieri, Rebecca L.; Campbell, Yvette; Roxas-Duncan, Virginia; Cardellina, John H.; Webb, Robert; Smith, Leonard A.

doi:10.1016/j.bmcl.2016.11.019

Cited by 10 publications

(7 citation statements)

References 20 publications

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“…However, since the substrate binding cleft of LC/A is unusually large, inhibitors with surface areas >200 Å 2 may be required for effective interaction with the active site cavity (Segelke et al, 2004). This is clearly beyond the purview of a typical SMI (Pang et al, 2009; Kumaran et al, 2015; Harrell et al, 2017). In this study, we report on the efficacy of the mercaptoacetamide inhibitor ABS 252 in enzymatic and biological assays and assess its ability to extend survival of mice in vivo .…”

Section: Introductionmentioning

confidence: 90%

“…This is due in part to the size and conformational flexibility of the BoNT active site and to the extensive binding interactions between BoNT/A LC (LC/A) and SNAP-25 (Chen et al, 2007; Bremer et al, 2017). Thus, crystal structure data suggest that the active site of LC/A has a great deal of conformational flexibility, making the design of highly potent SMI inhibitors challenging (Silvaggi et al, 2007; Kumaran et al, 2015; Harrell et al, 2017). Further complicating a small molecule approach is the presence of ancillary binding sites (exosites) that contribute to the tight binding of SNAP-25 to LC/A (Chen et al, 2007; Xue et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Jacobson¹,

Adler²,

Silvaggi

et al. 2017

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Botulinum neurotoxins (BoNTs) are the most toxic substances known to mankind and are the causative agents of the neuroparalytic disease botulism. Their ease of production and extreme toxicity have caused these neurotoxins to be classified as Tier 1 bioterrorist threat agents and have led to a sustained effort to develop countermeasures to treat intoxication in case of a bioterrorist attack. While timely administration of an approved antitoxin is effective in reducing the severity of botulism, reversing intoxication requires different strategies. In the present study, we evaluated ABS 252 and other mercaptoacetamide small molecule active-site inhibitors of BoNT/A light chain using an integrated multi-assay approach. ABS 252 showed inhibitory activity in enzymatic, cell-based and muscle activity assays, and importantly, produced a marked delay in time-to-death in mice. The results suggest that a multi-assay approach is an effective strategy for discovery of potential BoNT therapeutic candidates.

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Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Jacobson¹,

Adler²,

Silvaggi

et al. 2017

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“…658 A brief SAR study around BoNTi-22 led to the discovery of several other BoNT inhibitors. 665–667 Most notable of these was BoNTi-23. 659 This study found that the 2-position only accommodates small substitutients, and that the 5-position represents another site to further elaborate inhibitors.…”

Section: Peptidases (Ec 34)mentioning

confidence: 99%

“…BoNT has historically been a very difficult enzyme to target, 646 in part because the active site is highly flexible, making predictions for rational SAR difficult. 653,657,662,667,669,670 Furthermore, in vitro assays typically use the truncated light chain form of BoNT, with the heavy chain removed for safety; however, this single chain is less active than the native, two chain form. 641 The truncated enzyme used for in vitro assays is often not representative on the full-length metalloenzyme activity, and inhibitors generally display different activity in cellular and in vivo screening.…”

Section: Chemical Reviewsmentioning

confidence: 99%

Targeting Metalloenzymes for Therapeutic Intervention

et al. 2018

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Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many others. The role of metalloenzymes in these processes also makes them central for the progression of many diseases and, as such, makes metalloenzymes attractive targets for therapeutic intervention. Increasing awareness of the role metalloenzymes play in disease and their importance as a class of targets has amplified interest in the development of new strategies to develop inhibitors and ultimately useful drugs. In this Review, we provide a broad overview of several drug discovery efforts focused on metalloenzymes and attempt to map out the current landscape of high-value metalloenzyme targets.

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“…Several works have focused on the search of 7-substituted 8HQs with inhibitory activity against BoNTs (Figure ). − In the study of Roxas-Duncan et al, compound 45a was discovered, in a virtual screening, as an interesting BoNT/A LC inhibitor. However, the toxicity of this derivative in neuroblastoma N2a cells led to the search of analogues.…”

Section: Molecular Targets Of Antimicrobial 8hqsmentioning

confidence: 99%

Novel Antimicrobial 8-Hydroxyquinoline-Based Agents: Current Development, Structure–Activity Relationships, and Perspectives

et al. 2021

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The search for new antimicrobials is imperative due to the emergent resistance of new microorganism strains. In this context, revisiting known classes like 8-hydroxyquinolines could be an interesting strategy to discover new agents. The 8-hydroxyquinoline derivatives nitroxoline and clioquinol are used to treat microbial infections; however, these drugs are underused, being available in few countries or limited to topical use. After years of few advances, in the last two decades, the potent activity of clioquinol and nitroxoline against several targets and the privileged structure of 8-hydroxyquinoline nucleus have prompted an increased interest in the design of novel antimicrobial, anticancer, and anti-Alzheimer agents based on this class. Herein, we discuss the current development and antimicrobial structure–activity relationships of this class in the perspective of using the 8-hydroxyquinoline nucleus for the search for novel antimicrobial agents. Furthermore, the most investigated molecular targets concerning 8-hydroxyquinoline derivatives are explored in the final section.

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A matrix-focused structure-activity and binding site flexibility study of quinolinol inhibitors of botulinum neurotoxin serotype A

Cited by 10 publications

References 20 publications

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A

Targeting Metalloenzymes for Therapeutic Intervention

Novel Antimicrobial 8-Hydroxyquinoline-Based Agents: Current Development, Structure–Activity Relationships, and Perspectives

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