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Botulinum Neurotoxins and Botulism: A Novel Therapeutic Approach
AbstractSpecific treatment is not available for human botulism. Current remedial mainstay is the passive administration of polyclonal antibody to botulinum neurotoxin (BoNT) derived from heterologous species (immunized animal or mouse hybridoma) together with supportive and symptomatic management. The antibody works extracellularly, probably by blocking the binding of receptor binding (R) domain to the neuronal receptors; thus inhibiting cellular entry of the holo-BoNT. The antibody cannot neutralize the intracellular toxin. Moreover, a conventional antibody with relatively large molecular size (150 kDa) is not accessible to the enzymatic groove and, thus, cannot directly inhibit the BoNT zinc metalloprotease activity. Recently, a 15–20 kDa single domain antibody (VHH) that binds specifically to light chain of BoNT serotype A was produced from a humanized-camel VH/VHH phage display library. The VHH has high sequence homology (>80%) to the human VH and could block the enzymatic activity of the BoNT. Molecular docking revealed not only the interface binding between the VHH and the toxin but also an insertion of the VHH CDR3 into the toxin enzymatic pocket. It is envisaged that, by molecular linking the VHH to a cell penetrating peptide (CPP), the CPP-VHH fusion protein would be able to traverse the hydrophobic cell membrane into the cytoplasm and inhibit the intracellular BoNT. This presents a novel and safe immunotherapeutic strategy for botulism by using a cell penetrating, humanized-single domain antibody that inhibits the BoNT by means of a direct blockade of the groove of the menace enzyme.
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Thanongsaksrikul, J.; Chaicumpa, W. Botulinum Neurotoxins and Botulism: A Novel Therapeutic Approach. Toxins 2011, 3, 469-488.View more citation formats
Thanongsaksrikul J, Chaicumpa W. Botulinum Neurotoxins and Botulism: A Novel Therapeutic Approach. Toxins. 2011; 3(5):469-488.Chicago/Turabian Style
Thanongsaksrikul, Jeeraphong; Chaicumpa, Wanpen. 2011. "Botulinum Neurotoxins and Botulism: A Novel Therapeutic Approach." Toxins 3, no. 5: 469-488.