The evolving field of biodefence: therapeutic developments and diagnostics

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.

Figure 1. A schematic of anthrax toxin (ATX) lethal factor cell entry.

a | ATX is secreted by Bacillus anthracis. b | The inactive form of protective antigen (PA₈₃) binds to a host-cell receptor, where it is cleaved by a furin-related protease, to give active PA₆₃. c | PA₆₃ heptamerizes and can bind to either lethal factor (LF) or oedema factor (EF) (in this depiction the heptamer binds LF). d | The complex is endocytosed, and LF (as shown) or EF (not shown) translocates from the endosome into the host-cell cytosol. e | Therapeutics, in this example NSC 12155 (Ref. 19), are being designed to enter intoxicated cells and inhibit the protease activity of LF. f | A surface depiction of NSC 12155 bound within the LF substrate-binding cleft is shown. The inhibitor carbons are green, nitrogens are blue and oxygens are red. The surface of LF is red for acidic surface, blue for basic surface, and white for neutral surface.

Figure 2. Toxin interactions with inhibitors (a–c) or other proteins (d).

a | The co-crystal structure of NSC 12155 bound in the lethal factor (LF) substrate-binding cleft (PDB Ref Code = 1PWP). LF is shown in green ribbon. Residues of the LF catalytic engine are shown in stick. Carbon atoms are green; oxygen atoms are red; and nitrogen atoms are blue. NSC 12155 carbons are magenta. The inhibitor sits in close proximity to the enzyme's catalytic zinc (gold). b | Inhibitor Q2-15 docked in the botulinum neurotoxin serotype A (BoNT/A) light-chain (LC) substrate-binding cleft. The BoNT/A LC model is a dynamics conformation generated from the X-ray crystal structure of PDB ref code = 1E1H. Colours are as described for a. Additionally, enzyme residues are rendered in stick. Q2-15 carbons are magenta; and Q2-15 chloro substituents are light green. One of the 7-chloro-quinoline components interacts with the catalytic zinc of the enzyme, whereas the other binds in a pocket located behind the catalytic engine of the enzyme. c | The co-crystal structure of pteroic acid bound in the substrate-binding pocket of the ricin A chain (PDB Ref Code = 1BR6). Colours are as described for a and b. Red spheres are water molecules. d | The co-crystal structure of the SEB–HLA-DR1 interaction (PDB Ref Code = 1SEB). SEB is depicted as cyan ribbons and HLA-DR1 is depicted as green ribbons. The side chains of residues spanning the contact interface are shown in stick, with carbon colours corresponding to protein ribbon colour. Residue oxygens are red and nitrogens are blue.

Figure 3. A schematic of how components of the national laboratory response network (LRN) coordinate when detecting and diagnosing a biothreat agent.

a | Initial responders collect evidence, which is then sent to surveillance laboratories or to confirmatory laboratories directly (b,c). Cooperation between these laboratories facilitates first line response procedures. d | Further confirmation of agent type and area of distribution, is then conducted at national laboratories.