Abstract
Botulinum neurotoxins are highly effective therapeutic products. Their therapeutic success results from highly specific and potent inhibition of neurotransmitter release with a duration of action measured in months. These same properties, however, make the botulinum neurotoxins the most potent acute lethal toxins known. Their toxicity and restricted target cell activity severely limits their clinical utility. Understanding the structure-function relationship of the neurotoxins has enabled the development of recombinant proteins selectively incorporating specific aspects of their pharmacology. The resulting proteins are not neurotoxins, but a new class of biopharmaceuticals, Targeted Secretion Inhibitors (TSI), suitable for the treatment of a wide range of diseases where secretion plays a major role. TSI proteins inhibit secretion for a prolonged period following a single application, making them particularly suited to the treatment of chronic diseases. A TSI for the treatment of chronic pain is in clinical development.
Highlights
Botulinum neurotoxins (BoNTs) are clinically valuable for treating various neuromuscular and autonomic conditions, and, as clinical products, have sales of more than a billion U.S dollars [1].Neurotoxins are clinically effective because they are potent and selective inhibitors of acetylcholine (ACh) release from peripheral nerves, and have a duration of action following a single administration that is often measured in months [2]
Novel recombinant proteins are entering the clinic that deliver the benefits of the neurotoxin pharmacology to a wider range of clinical applications without the inherent toxicity of the native neurotoxins
The di-chain clostridial neurotoxins (CNTs) protein consists of a light chain (LC) of approximately 50 kDa and a heavy chain (HC) of approximately 100 kDa [64]
Summary
Botulinum neurotoxins (BoNTs) are clinically valuable for treating various neuromuscular and autonomic conditions, and, as clinical products, have sales of more than a billion U.S dollars [1]. Despite targeting a universal mechanism of secretion in eukaryotic cells, the cellular selectivity of the neurotoxins limits their use to treating conditions involving cholinergic nerve activity. There exists, an opportunity to engineer novel proteins which retain the desirable pharmacological activities of the neurotoxins while reducing their toxicity and broadening their range of therapeutic applications. Novel recombinant proteins are entering the clinic that deliver the benefits of the neurotoxin pharmacology to a wider range of clinical applications without the inherent toxicity of the native neurotoxins. These developments are opening up a new generation of potent biologics for treating chronic diseases
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