Variability of Botulinum Toxins: Challenges and Opportunities for the Future

Abstract

Botulinum neurotoxins (BoNTs) are the most potent known toxins, and are therefore classified as extremely harmful biological weapons. However, BoNTs are therapeutic drugs that are widely used and have an increasing number of applications. BoNTs show a high diversity and are divided into multiple types and subtypes. Better understanding of the activity at the molecular and clinical levels of the natural BoNT variants as well as the development of BoNT-based chimeric molecules opens the door to novel medical applications such as silencing the sensory neurons at targeted areas and dermal restoration. This short review is focused on BoNTs' variability and the opportunities or challenges posed for future clinical applications.

Keywords: BoNT variants; botulinum neurotoxins (BoNTs); subtypes.

Figure 1

Structure of botulinum neurotoxins (BoNT)/A (pdb 3BTA) and BoNT/E (pdb 3FFZ): The catalytic domain (Lc) is colored in blue, the translocation domain (Hn) is colored in red, the N-terminal binding sub-domain (HcN) is colored in green, and the C-terminal binding sub-domain (HcC) is colored in yellow. The catalytic zinc site is depicted as a ball in magenta. Figures were produced with the program MacPymol.

Figure 2

Route and mechanism of intoxication by BoNT. (1) BoNTs and BoNT-hemagglutinin (HA) are transcytosed through epithelial and microfold (M) cells respectively in human intestinal epithelia; (2) In the extracellular region, the trimeric HA complexes bind to E-cadherin, leading to intestinal barrier disruption and paracellular passage; (3 and 4) BoNTs enter into the circulatory system and reach nerve terminals by an unknown way; (5) BoNTs bind to polysialoganglioside (PSG) and synaptic vesicle glycoprotein 2 (SV2); and enter neurons via clathrin-dependent endocytosis; (6) Hn domains form translocation channels for Lc to escape the endosomal acidic environment toward the neutral cytosol where the Lc is activated as a Zn²⁺-dependent protease; (7) The Lc protease cleaves SNAP-25 with extremely high specificity to block the synaptic vesicle traffic and neurotransmitter release.