Engineered type e botulinum neurotoxin for therapeutic and cosmetic applications

Abstract

Serotype E botulinum neurotoxin (BoNT/E) is one of the major causes of human botulism and paradoxically also a promising therapeutic agent. However, the molecular mechanism by which BoNT/E recognizes synaptic vesicle glycoprotein 2A (SV2.A) and 2B (SV2B), but no closely related SV2C, as its neuronal receptors has been challenging to resolve. The Inventor, surprisingly, was able to obtain crystal structures of the receptor-binding domain of BoNT/E (HCE) in complex with SV2.A. These structures reveal that HCE engages both specific peptide fragments and an N-glycan of SV2A, as well as SV2B in a similar manner. Structure-based mutagenesis and functional studies demonstrate that both the peptide- and glycan-based associations are essential for SV2A/2B-mediated cell entry of BoNT/E and for its potent neurotoxicity. Thus, the engineering of BoNT/E variants for new clinical applications is described herein.

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