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  • Review Article
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The evolving field of biodefence: therapeutic developments and diagnostics

Nature Reviews Drug Discovery volume 4, pages 281–296 (2005)Cite this article

Key Points

  • Bioweapons are a clear threat to both military and civilian populations. Here, the latest advances in the pursuit of inhibitors against biothreat threat toxins, current therapeutic strategies for treating biodefence related pathogens, and strategies for improving detection and exposure survivability are covered.

  • There are numerous lead therapeutics that have emerged from drug discovery efforts. However, many of these are toxic and/or fail to possess conventional drug-like properties. One clear advantage of small (non-peptidic) molecules is that they possess scaffolds that are inherently more likely to evolve into real therapeutics.

  • One of the major obstacles impeding the translation of these lead therapeutics into viable drugs is the lack of involvement of the pharmaceutical industry, which has been discovering leads and translating them into drugs for decades. The expertise of the pharmaceutical industry therefore needs to be more effectively engaged in developing drugs against biothreat agents.

  • New methods for rapidly detecting and diagnosing biothreat agents are also in development. The detection and diagnosis of biothreats is inherently linked with treatment. The means for detecting the release of bioweapons are being deployed, and new technologies are shortening the timeframe between initial sample collection and conclusive agent determination. However, the organization of this process is imperfect.

  • At present, a unifying entity that orchestrates the biodefence response is clearly needed to reduce the time-to-drug process and redundancies in drug development efforts. Such a central entity could formulate and implement plans to coordinate all participants, including academic institutions, government agencies and the private sector. This could accelerate the development of countermeasures against high probability biothreat agents.

Abstract

The threat of bioterrorism and the potential use of biological weapons against both military and civilian populations has become a major concern for governments around the world. For example, in 2001 anthrax-tainted letters resulted in several deaths, caused widespread public panic and exerted a heavy economic toll. If such a small-scale act of bioterrorism could have such a huge impact, then the effects of a large-scale attack would be catastrophic. This review covers recent progress in developing therapeutic countermeasures against, and diagnostics for, such agents.

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Figure 1: A schematic of anthrax toxin (ATX) lethal factor cell entry.
Figure 2: Toxin interactions with inhibitors (a–c) or other proteins (d).
Figure 3: A schematic of how components of the national laboratory response network (LRN) coordinate when detecting and diagnosing a biothreat agent.

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Acknowledgements

The authors would like to thank M. J. Aman, R. Panchal, C. Whitehouse, B. Purcell, B. Stiles, R. Gussio and M. Hepburn for critical comments and substantial help in preparing this review. T. L. Nguyen for generating figure 1. In addition, we sincerely apologise to our esteemed colleagues whose work could not be included in this review due to space limitations. The content of this review does not necessarily reflect the views or policies of the Department of Health and Human Services or US Army, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

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  1. Developmental Therapeutics Program, Target Structure-Based Drug Discovery Group, National Cancer Institute-SAIC, Frederick, 21702, Maryland, USA

    James C. Burnett

  2. United States Army Medical Research Institute of Infectious Diseases, Frederick, 21702, Maryland, USA

    Erik A. Henchal, Alan L. Schmaljohn & Sina Bavari

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Glossary

BACILLUS ANTHRACIS

The causative agent of anthrax and a Gram-positive, spore-forming bacillus. This aerobic organism is non-motile, catalase positive and forms large, grey–white to white, non-haemolytic colonies on sheep blood agar plates.

ANTHRAX TOXIN

A complex composed of three proteins: protective antigen (PA), lethal factor (LF) and oedema factor (EF).

SNARE COMPLEX

A complex composed of SNAP25, VAMP (also referred to as synaptobrevin) and syntaxin that is involved in membrane fusion and the exocytosis of acetylcholine into neuromuscular junctions.

RICIN TOXIN

Isolated from seeds of the castor plant (Ricinus communis), ricin toxin consists of a 32-kDa B chain that is linked by a disulphide bridge to a 32-kDa A chain (RTA)175,176. The B chain binds cell surfaces. Once inside the cell cytoplasm, RTA is released, and irreversibly depurinates the 28S rRNA, destroying the elongation-factor-binding site, and thereby disabling cellular protein synthesis177,178,179.

STAPHYLOCOCCAL ENTEROTOXINS

A large group of protein toxins that engage both major histocompatibility complex class II molecules on the surface of antigen-presenting cells and the variable (V) β-chain of a large subset of T-cell receptors.

YERSINIA PESTIS

The causative agent of plague, it is an aerobic, Gram-negative bacillus from the bacterial family Enterobacteriaceae.

FRANCESELLA TULARENSIS

The causative agent of tularaemia, it is a small, aerobic Gram-negative coccobacilli. This agent is the most infectious human pathogen known. In the past, both the former Soviet Union and the US had programmes to develop weapons containing this bacterium.

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Burnett, J., Henchal, E., Schmaljohn, A. et al. The evolving field of biodefence: therapeutic developments and diagnostics. Nat Rev Drug Discov 4, 281–296 (2005). https://doi.org/10.1038/nrd1694

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