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Botulinum neurotoxin, commercialized as anti-wrinkle agents and famous for Botox, acts by
cleaving SNARE proteins at neuromuscular junction. In the cascade of neurotransmission, euronal SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins play a central role, where neurotransmitter release requires the synaptic vesicles SNARE protein VAMP2, and the plasma membrane SNARE proteins syntaxin 1 and SNAP-25 at the neuronal terminal. These proteins assemble in to a highly stable, ternary complex known as the SNARE complex. Cumulative evidence has shown that this protein complex generates fundamental force that is required for the membrane fusion. By the result of synaptic membrane fusion, a fusion pore is made, through which neurotransmitters are released. SNARE proteins are specific targets of clostridial neurotoxins, which inhibit neurotransmitter release without altering synaptic vesicle docking. Neurotransmission can be controlled by regulating SNARE assembly, leading to the prevention of wrinkle formation by muscle contraction. For example, Botox is a popular cosmetic agent used to reduce the size of wrinkle. The action mechanism of Botox is to cleave SNARE proteins disabling neurotransmission. If neurotransmission is disabled, muscle cannot contract or relax, thus, wrinkle cannot be formed. In order to regulate SNARE assembly, rather than cleaving, we screened and developed SNARE folding inhibitors from peptide, plant extracts and chemical compounds. First, we have designed small peptides that appear to be suitable candidates to modulate the formation of ternary complex in α- helical second structure. We could find some synthetic peptides that were more potent to inhibit, than the well-known “Argirelline”, SNARE complex assembly and neuronal exocytosis. However, their high cost seriously limits their use. Second, we drew some candidate materials from plant extracts. High-throughput screening technology has been developed and initially 100 kinds of plant extracts have been tested for their membrane fusion inhibition efficacy. The found materials might function as anti-wrinkle agent by blocking SNARE complex while Botox cleaves SNARE proteins. Finally we
could draw some candidate SNARE folding modulator from phenolic compounds derived from plant extracts. A few compounds inhibited SDS-resistant SNARE complex formation and neurotransmitter release by membrane fusion prevention in PC12 cells. Probably, the found materials may play a role as an effective anti-wrinkle agent when combined with efficient delivery system.