ObjectiveThe Working Group on Civilian Biodefense has developed consensus-based
recommendations for measures to be taken by medical and public health professionals
if botulinum toxin is used as a biological weapon against a civilian population.ParticipantsThe working group included 23 representatives from academic, government,
and private institutions with expertise in public health, emergency management,
and clinical medicine.EvidenceThe primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE
(1960–March 1999) and their professional collections for literature
concerning use of botulinum toxin as a bioweapon. The literature was reviewed,
and opinions were sought from the working group and other experts on diagnosis
and management of botulism. Additional MEDLINE searches were conducted through
April 2000 during the review and revisions of the consensus statement.Consensus ProcessThe first draft of the working group's consensus statement was a synthesis
of information obtained in the formal evidence-gathering process. The working
group convened to review the first draft in May 1999. Working group members
reviewed subsequent drafts and suggested additional revisions. The final statement
incorporates all relevant evidence obtained in the literature search in conjunction
with final consensus recommendations supported by all working group members.ConclusionsAn aerosolized or foodborne botulinum toxin weapon would cause acute
symmetric, descending flaccid paralysis with prominent bulbar palsies such
as diplopia, dysarthria, dysphonia, and dysphagia that would typically present
12 to 72 hours after exposure. Effective response to a deliberate release
of botulinum toxin will depend on timely clinical diagnosis, case reporting,
and epidemiological investigation. Persons potentially exposed to botulinum
toxin should be closely observed, and those with signs of botulism require
prompt treatment with antitoxin and supportive care that may include assisted
ventilation for weeks or months. Treatment with antitoxin should not be delayed
for microbiological testing.

https://jamanetwork.com/journals/JAMA/articlepdf/193600/jst00017.pdf

Botulinum Toxin as a Biological Weapon: Medical and Public Health Management

Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here. These neurotoxins can be grouped in three large families: 1) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2) the snake presynaptic neurotoxins with phospholipase A(2) activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses. Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause. The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals.

https://www.physiology.org/doi/pdf/10.1152/physrev.2000.80.2.717

Neurotoxins Affecting Neuroexocytosis

Botulinum neurotoxin type A (BoNT/A) is the potent disease agent in botulism, a potential biological weapon and an effective therapeutic drug for involuntary muscle disorders. The crystal structure of the entire 1,285 amino acid di-chain neurotoxin was determined at 3.3 A resolution. The structure reveals that the translocation domain contains a central pair of alpha-helices 105 A long and a approximately 50 residue loop or belt that wraps around the catalytic domain. This belt partially occludes a large channel leading to a buried, negative active site--a feature that calls for radically different inhibitor design strategies from those currently used. The fold of the translocation domain suggests a mechanism of pore formation different from other toxins. Lastly, the toxin appears as a hybrid of varied structural motifs and suggests a modular assembly of functional subunits to yield pathogenesis.

Crystal structure of botulinum neurotoxin type A and implications for toxicity.

Structure–function relationships of immunostimulatory polysaccharides: A review

Motivation The identification of novel drug-target (DT) interactions is a substantial part of the drug discovery process. Most of the computational methods that have been proposed to predict DT interactions have focused on binary classification, where the goal is to determine whether a DT pair interacts or not. However, protein-ligand interactions assume a continuum of binding strength values, also called binding affinity and predicting this value still remains a challenge. The increase in the affinity data available in DT knowledge-bases allows the use of advanced learning techniques such as deep learning architectures in the prediction of binding affinities. In this study, we propose a deep-learning based model that uses only sequence information of both targets and drugs to predict DT interaction binding affinities. The few studies that focus on DT binding affinity prediction use either 3D structures of protein-ligand complexes or 2D features of compounds. One novel approach used in this work is the modeling of protein sequences and compound 1D representations with convolutional neural networks (CNNs). Results The results show that the proposed deep learning based model that uses the 1D representations of targets and drugs is an effective approach for drug target binding affinity prediction. The model in which high-level representations of a drug and a target are constructed via CNNs achieved the best Concordance Index (CI) performance in one of our larger benchmark datasets, outperforming the KronRLS algorithm and SimBoost, a state-of-the-art method for DT binding affinity prediction. Availability and implementation https://github.com/hkmztrk/DeepDTA. Supplementary information Supplementary data are available at Bioinformatics online.

DeepDTA: deep drug–target binding affinity prediction

Structural predictions of the channel-forming region of botulinum neurotoxin heavy chain

Antagonism of botulinum toxin-induced muscle weakness by 3,4-diaminopyridine in rat phrenic nerve-hemidiaphragm preparations

The botulinum neurotoxins (BoNT, serotypes A-G) are some of the most toxic proteins known and are the causative agents of botulism. Following exposure, the neurotoxin binds and enters peripheral cholinergic nerve endings and specifically and selectively cleaves one or more SNARE proteins to produce flaccid paralysis. This review centers on the kinetics of the Zn-dependent proteolytic activities of these neurotoxins, and briefly describes inhibitors, activators and factors underlying persistence of toxin action. Some of the structural, enzymatic and inhibitor data that are discussed here are available at the botulinum neurotoxin resource, BotDB (http://botdb.abcc.ncifcrf.gov).

https://www.mdpi.com/2072-6651/2/5/978/pdf

The Zinc-Dependent Protease Activity of the Botulinum Neurotoxins

The deployment of biological and chemical weapons by aggressor states is not a hypothetical scenario but a life-threatening contingency. Although Iraq was deterred from using its biological and chemical weapons during Operation Desert Storm, what forms of deterrence must be considered in preventing the use of these weapons of mass destruction in the future? Traditional deterrents against their use have ranged from the threat of a military response to the ratification of diplomatic treaties and agreements. An overall strategy to deter the use of these weapons includes an additional, less frequently discussed approach-force protection-which encompasses defensive biomedical countermeasures (e.g., antibiotics, drugs, vaccines, diagnostic tests) and nonmedical protective devices (e.g., masks, specialized clothing/shelters, detectors). A combined, integrated approach to deterrence is reviewed in this article with regard to current policies and the roles played by Department of Defense research and development programs for biological and chemical defense.

/pdf/deterrence-of-biological-and-chemical-warfare-a-review-of-1xha0b2hc8.pdf

Deterrence of biological and chemical warfare: a review of policy options.

This review centers on the structure and function of ionic channels formed by clostridial neurotoxins. Questions regarding their structure, the pathways for their formation, and their role in translocating the toxic moiety across an endocytotic membrane are discussed.

Frank J. Lebeda

Papers

Structural predictions of the channel-forming region of botulinum neurotoxin heavy chain

Antagonism of botulinum toxin-induced muscle weakness by 3,4-diaminopyridine in rat phrenic nerve-hemidiaphragm preparations

The Zinc-Dependent Protease Activity of the Botulinum Neurotoxins

Deterrence of biological and chemical warfare: a review of policy options.

Membrane Channel activity and Translocation of Tetanus and Botulinum Neurotoxins