Structure-Based Drug Discovery for Botulinum Neurotoxins
Biology Department, Brookhaven National Laboratory, Upton, NY, 11973, USA, .Current topics in microbiology and immunology (Impact Factor: 4.1). 01/2013; 364:197-218. DOI: 10.1007/978-3-642-33570-9_10
Clostridium botulinum neurotoxin is the most poisonous substance known to humans. It is a potential biowarfare threat and a public health hazard. The only therapeutics available is antibody treatment which will not be effective for post-exposure therapy. There are no drugs available for post-intoxication treatment. Accordingly, it is imperative to develop effective drugs to counter botulism. Available structural information on botulinum neurotoxins both alone and in complex with their substrates offers an efficient method for designing structure-based drugs to treat botulism.
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ABSTRACT: This chapter summarizes the known pathophysiological and molecular actions on nerve terminals and nerve tissue of several potent toxins produced by Clostridium species. This includes the botulinum and tetanus neurotoxins, which are to date the best documented toxins acting on neurotransmitter release. These toxins can indiscriminately damage membranes from different cells, including those of neuronal origin. Among them, C. perfringens epsilon toxin has the fundamental structure of a pore-forming toxin, is cytotoxic for kidney epithelial cells, and also possesses specific neurotoxic activity. Other toxins have developed various internalization processes, therefore specifically modifying an intracellular target. Thus, several bacterial proteins like the large clostridial toxins have the ability to bind/enter various cell types that include those of neuronal origin. During their evolution, clostridial pathogens have developed a potent arsenal of noxious proteins thataffect the central and peripheral nervous system of various vertebrates. These commonly named neurotoxins specifically target some key functions, or cellular processes, of eukaryotic cells, which subsequently cause a wide array of life-threatening diseases in humans and animals. The specificity of these toxic proteins has enabled them to become useful tools to elucidate and characterize crucial processes for eukaryotic cells, which include neurotransmitter release, physiological signaling pathways, and constitutive cellular mechanisms. Additional studies are needed to completely identify their specific membrane-receptors, as well as comprehend the mechanisms and structures involved in toxin routing throughout the nervous system.
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ABSTRACT: Botulism is a severe neuroparalytic disease resulting from exposure to one of the most poisonous toxins to humans. Because of this high potency and the use of toxins as biological weapons, botulism is a public health concern and each case represents an emergency. Current therapy involves respiratory supportive care and anti-toxins administration. As a preventive measure, vaccination against toxins represents an effective strategy but is undesirable due the rarity of botulism and the effectiveness of toxins in treating several neuromuscular disorders. This paper summarizes the current issues in botulism treatment and prevention, highlighting the challenge for future researches.
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