Identification of SNARE complex modulators that inhibit exocytosis from an alpha-helix-constrained combinatorial library.

Synthetic peptides patterned after the proteins involved in vesicle fusion [the so-called SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) proteins] are potent inhibitors of SNARE complex assembly and neuronal exocytosis. It is noteworthy that the identification of peptide sequences not related to the SNARE proteins has not been accomplished yet; this is due, in part, to the structural constraints and the specificity of the protein interactions that govern the formation of the SNARE complex. Here we have addressed this question and used a combinatorial approach to identify peptides that modulate the assembly of the SNARE core complex and inhibit neuronal…