Therapy and prophylaxis of inhaled biological toxins

Abstract

This review highlights the current lack of therapeutic and prophylactic treatments for use against inhaled biological toxins, especially those considered as potential biological warfare (BW) or terrorist threats. Although vaccine development remains a priority, the use of rapidly deployable adjunctive therapeutic or prophylactic drugs could be life-saving in severe cases of intoxication or where vaccination has not been possible or immunity not established. The current lack of such drugs is due to many factors. Thus, methods involving molecular modelling are limited by the extent to which the cellular receptor sites and mode of action and structure of a toxin need to be known. There is also our general lack of knowledge of what effect individual toxins will have when inhaled into the lungs - whether and to what extent the action will be cell specific and cytotoxic or rather an acute inflammatory response requiring the use of immunomodulators. Possible sources of specific high-affinity toxin antagonists being investigated include monoclonal antibodies, selected oligonucleotides (aptamers) and derivatized dendritic polymers (dendrimers). The initial selection of suitable agents of these kinds can be made using cytotoxicity assays involving cultured normal human lung cells and a range of suitable indicators. The possibility that a mixture of selected antibody, aptamer or dendrimer-based materials for one or more toxins could be delivered simultaneously as injections or as inhaled aerosol sprays should be investigated.

A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

“…It is important to note that the eight-component pharmacophore model presented in Figure 1A is a logical extension of the six-component model shown in our original work 31 and is part of an ongoing refinement of our pharmacophore for BoNT/A LC inhibition 32,33 (which is occurring as more data become available). In this study, we wanted to identify compounds containing as many pharmacophore features as possible, but with the following specific components: (1) the ACQ substructure (which incorporates pharmacophore components A, a heteroatom associated with A, and C ( Figure 1A)), (2) an ionizable amine located 6.5-9.5 Å from the centroid of the ACQ (pharmacophore component E ( Figure 1A)), and (3) at least one of the new components from our expanded pharmacophore, either F 33 (a positive ionizable moiety located 11.7-16.7 Å from the quinoline centroid) or G 33 (a hydrophobic moiety located 8.5-12.5 Å from the quinoline centroid) ( Figure 1A). Subsequently, a congeneric series of 4-amino-7-chloroquinoline-cholate-acetates, 1-3, and a tri-ACQ derivative, 4, were identified (see Scheme 1 for two-dimensional (2-D) structures of 1-3 and Figure 2 for the 2-D structure of 4).…”

“…1,2 As a result, these enzymes, which are responsible for the paralysis associated with botulism, are listed as category A (highest priority) biothreat agents by the Centers for Disease Control and Prevention (CDC). BoNTs are easily produced and may be delivered via food "spiking" and/or aerosol route.…”

“…BoNTs are easily produced and may be delivered via food "spiking" and/or aerosol route. [2][3][4][5][6] Furthermore, as BoNTs are now used to treat a range of medical conditions, and in many cosmetic applications, 3,[7][8][9][10][11][12][13][14] they are being produced in increasing quantities, making their misuse, accidental overdosing, and/or instances of adverse side effects 15 more likely. Neither the currently available CDC BoNT equine antitoxins, which can cause adverse anaphylaxis and serum sickness, 16 nor experimental antibodies can counter these enzymes once they are inside neurons.…”

Strategies and Methods for Investigation of Airborne Biological Agents From Work Environments in Germany

“…It is well known that metabolic substances or microbial spores themselves may cause allergic symptoms. Furthermore, under certain conditions some biological agents may produce chemical substances which can cause pathogenic effects in the host by poisoning (exotoxins, endotoxins and mycotoxins) [8]. These substances of biological origin are not biological agents according to the definition given in Directive 2000/54/EC [1].…”

The Akt Pathway Inhibitor Degeulin Prevents Staphylococcal Enterotoxin B Induced Splenocyte Proliferation and Inflammation

“…For this reason, it is considered a potential biological weapon [10] [11]. Clinical signs of intoxication are to some extent dependent on the route of exposure with onset starting 1 to 6 hours after exposure [12]. Signs of inhalational intoxication include fever, respiratory problems, gastrointestinal (GI) symptoms, toxic or septic shock and death [13].…”