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

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:
 [1] ;  [2]
  1. Brookhaven National Lab. (BNL), Upton, NY (United States); St. Jude Research Hospital, Memphis, TN (United States)
  2. Brookhaven National Lab. (BNL), Upton, NY (United States)
Publication Date:
OSTI Identifier:
1183824
Report Number(s):
BNL--107809-2015-JA
Journal ID: ISSN 1568-0266; 400403709
Grant/Contract Number:
SC00112704
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
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE; Defense Threat Reduction Agency (DTRA)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES bioterrorism; Clostridium botulinum; Neurotoxin; drug discovery; Protease inhibitor