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OwnerHaruo Kasai, Noriko Takahashi +3inventors
InventorsHaruo Kasai, Noriko Takahashi, Vesa Olkkonen, Herbert Y. Gaisano, Patrick Lam
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Munc18 proteins facilitate formation of SNARE complexes known to mediate membrane fusion. Much is known about the fusion of secretory granule (SG) to plasma membrane, mediated by Munc18a-SNARE complexes. It has been found that another Munc18 isoform, Munc18b, mediates SG-SG fusion which causes potentiation of secretion. The present invention has identified specific site mutations within Munc18b which further increased (called KR mutant) or reduced (called E59K mutant) SG-SG fusion compared to wild type (WT) Munc18b, causing amplification or reduction of insulin secretion, respectively. Compounds identified that mimic the actions of Munc18b-WT and Munc18b-KR mutant which increase SG-SG fusion, and those which mimic Munc18b-E59K mutant that block SG-SG fusion, are useful for treating and/or preventing diseases and/or conditions, whose underlying bases are a deficiency or excess of SG-SG fusion, respectively. These compounds also include conserved domains in Munc18a and Munc18c that mimic the KR and E59K sites in Munc18b.
The compounds that mimic the mutation within the protein Munc18b, Munc18b K314L/R315L (Munc18b-KR) in whole or in part, whose biochemical action is to enhance complex formation with Syntaxins (Syntaxin-2 and Syntaxin-3 primarily, and also Syntaxin-1) in a manner that induces SNARE complex assembly (with the families of VAMP and SNAP-25 proteins);
The compounds that mimic the mutation within the Munc18b protein, Munc18b E59K in whole or in part, whose biochemical action is to reduce complex formation with Syntaxins (Syntaxin-2 and Syntaxin-3 primarily, and also Syntaxin 1), in a manner that reduces SNARE complex assembly (with the families of VAMP and SNAP-25 proteins);
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