Inhibition of Secretion
Secretion as a target
Vesicular secretion, particularly regulated secretion, is a key component of how cells interact with each other and with their environment. As such, it plays a critical role in the physiology of multicellular organisms. Given its physiological importance, it is not surprising that vesicular secretion plays a significant causative or contributing role in a wide range of diseases and medical conditions. For example, the release of acetylcholine from peripheral motor nerves drives muscle contraction involved in a variety of movement disorders and spastic conditions.
Similarly, the release of neuropeptides and neurotransmitters from the synapses of nociceptive afferent nerves drives pain responses in a variety of conditions. Such secretion also plays a significant part in neurogenic inflammation and tissue hypersensitivity. Release of hormones by endocrine cells is a major regulator of metabolism and its dysfunction underpins a wide range of metabolic and endocrine disorders. Secretion of hormones and growth factors - both paracrine and autocrine - also plays a significant role in the development and maintenance of tumours.
Fusion of intracellular vesicles with the plasma membrane underpins not only the release of secreted materials from the cell, but also the regulated cell surface expression of many important membrane proteins, for example; receptors, transporters and ion channels.
It is therefore clear that vesicular secretion is a fundamental cell function with relevance to a very large number of diseases and medical conditions. Syntaxin’s unique expertise is in knowledge of endopeptidases that cleave essential components of the cell secretion apparatus. The ability to construct novel recombinant proteins that target specific cell secretion pathways resulting in reversible, non-cytotoxic, long duration of action inhibition of cell secretion. These proteins are Syntaxin’s TSI.
View how botulinum neurotoxin blocks cholinergic transmission at the neuromuscular junction
Role of SNARE Proteins and clostridial neurotoxins
Vesicle fusion, therefore vesicular secretion, within cells is driven by a set of proteins called SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. SNARE proteins are a family of membrane proteins found in vesicle and cell membranes.
The prototypic neuronal SNARE proteins consist of the vesicle associated membrane protein (VAMP or synaptobrevin) and the synaptic membrane proteins syntaxin 1 and SNAP-25. The SNARE proteins form a tetra-helical complex that dock and fuse vesicles with their target membrane. SNARE proteins are essential for the docking and fusion of vesicles with membranes not just in nerve cells but in all eukaryotic cells. It is the SNARE proteins involved in vesicular secretion that are the target for Syntaxin’s TSI.
Clostridial neurotoxins, including the botulinum neurotoxins are potent inhibitors of the vesicular secretion of neurotransmitters from nerve cells, particularly acetylcholine at the neuromuscular junction, via proteolytic cleavage of SNARE proteins. The potent and selective inhibition of acetylcholine release from the peripheral terminals of motor-neurones by botulinum neurotoxins results in a profound muscle relaxation, which had initial clinical application in the treatment of muscular dystonias.
Subsequently, the clinical use of neurotoxin has expanded to other neuromuscular applications and also to hypersecretory disorders of the autonomic nervous system, including hyperhydrosis. Clinical preparations of botulinum neurotoxin are now major biotherapeutic products with sales exceeding $1.5bn.
The endopeptidase activity of clostridial neurotoxins forms the basis of Syntaxin’s TSI.