Recent developments with metalloprotease inhibitor class of drug candidates for Botulinum neurotoxins

Kumar, Gyanendra; Swaminathan, Subramanyam

doi:10.2174/1568026615666150309150338

Title: Recent developments with metalloprotease inhibitor class of drug candidates for Botulinum neurotoxins

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Abstract

Botulinum Neurotoxins are the most poisonous of all toxins with lethal dose in nanogram quantities. They are also potential biological warfare and bioterrorism agents due to their high toxicity and ease of preparation. On the other hand BoNTs are also being increasingly used for therapeutic and cosmetic purposes, and with that the chances of accidental overdose are increasing. And despite the potential damage they could cause to human health, there are no post-intoxication drugs available so far. But progress is being made in this direction. The crystal structures in native form and bound with substrate peptides have been determined, and these are enabling structure-based drug discovery possible. High throughput assays have also been designed to speed up the screening progress. Substrate-based and small molecule inhibitors have been identified. But turning high affinity inhibitors into clinically viable drug candidates has remained a challenge. We discuss here the latest developments and the future challenges in drug discovery for Botulinum neurotoxins.

Authors:

Kumar, Gyanendra ^[1]; Swaminathan, Subramanyam ^[2]

Brookhaven National Lab. (BNL), Upton, NY (United States); St. Jude Research Hospital, Memphis, TN (United States)
Brookhaven National Lab. (BNL), Upton, NY (United States)

Publication Date:: Sun Mar 01 00:00:00 EST 2015

Research Org.:: Brookhaven National Lab. (BNL), Upton, NY (United States)

Sponsoring Org.:: USDOE; Defense Threat Reduction Agency (DTRA)

OSTI Identifier:: 1183824

Report Number(s):: BNL-107809-2015-JA
Journal ID: ISSN 1568-0266; 400403709

Grant/Contract Number:: SC00112704

Resource Type:: Accepted Manuscript

Journal Name:: Current Topics in Medicinal Chemistry

Additional Journal Information:: Journal Volume: 15; Journal Issue: 7; Journal ID: ISSN 1568-0266

Publisher:: Bentham Science

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; bioterrorism; Clostridium botulinum; Neurotoxin; drug discovery; Protease inhibitor

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                    Kumar, Gyanendra, and Swaminathan, Subramanyam. Recent developments with metalloprotease inhibitor class of drug candidates for Botulinum neurotoxins.  United States: N. p., 2015. 
Web.  doi:10.2174/1568026615666150309150338.

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                    Kumar, Gyanendra, & Swaminathan, Subramanyam. Recent developments with metalloprotease inhibitor class of drug candidates for Botulinum neurotoxins.  United States.  https://doi.org/10.2174/1568026615666150309150338

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                    Kumar, Gyanendra, and Swaminathan, Subramanyam. Sun .  
"Recent developments with metalloprotease inhibitor class of drug candidates for Botulinum neurotoxins".  United States.  https://doi.org/10.2174/1568026615666150309150338.  https://www.osti.gov/servlets/purl/1183824.

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@article{osti_1183824,

  title        = {Recent developments with metalloprotease inhibitor class of drug candidates for Botulinum neurotoxins},

  author       = {Kumar, Gyanendra and Swaminathan, Subramanyam},

  abstractNote = {Botulinum Neurotoxins are the most poisonous of all toxins with lethal dose in nanogram quantities. They are also potential biological warfare and bioterrorism agents due to their high toxicity and ease of preparation. On the other hand BoNTs are also being increasingly used for therapeutic and cosmetic purposes, and with that the chances of accidental overdose are increasing. And despite the potential damage they could cause to human health, there are no post-intoxication drugs available so far. But progress is being made in this direction. The crystal structures in native form and bound with substrate peptides have been determined, and these are enabling structure-based drug discovery possible. High throughput assays have also been designed to speed up the screening progress. Substrate-based and small molecule inhibitors have been identified. But turning high affinity inhibitors into clinically viable drug candidates has remained a challenge. We discuss here the latest developments and the future challenges in drug discovery for Botulinum neurotoxins.},

  doi          = {10.2174/1568026615666150309150338},

  journal      = {Current Topics in Medicinal Chemistry},

  number       = 7,

  volume       = 15,

  place        = {United States},

  year         = {Sun Mar 01 00:00:00 EST 2015},

  month        = {Sun Mar 01 00:00:00 EST 2015}

}

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