Abstract
Although botulinum neurotoxin serotype A (BoNT/A) products are common treatments for various disorders, there is only one commercial BoNT/B product, whose low potency, likely stemming from low affinity toward its human receptor synaptotagmin 2 (hSyt2), has limited its therapeutic usefulness. We express and characterize two full-length recombinant BoNT/B1 proteins containing designed mutations E1191M/S1199Y (rBoNT/B1 MY ) and E1191Q/S1199W (rBoNT/B1 QW ) that enhance binding to hSyt2. In preclinical models including human-induced pluripotent stem cell neurons and a humanized transgenic mouse, this increased hSyt2 affinity results in high potency, comparable to that of BoNT/A. Last, we solve the cocrystal structure of rBoNT/B1 MY in complex with peptides of hSyt2 and its homolog hSyt1. We demonstrate that neuronal surface receptor binding limits the clinical efficacy of unmodified BoNT/B and that modified BoNT/B proteins have promising clinical potential.
Original language | English |
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Article number | eaau7196 |
Pages (from-to) | 1-13 |
Number of pages | 13 |
Journal | Science Advances |
Volume | 5 |
Issue number | 1 |
DOIs | |
Publication status | Published - 16 Jan 2019 |
Funding
We thank J.-L. Blachon (Ipsen) for help with the statistical analysis and M. Norbert (genOway) for help with compiling the husbandry data for the hSyt2 mice. We thank the scientists at stations I02, I03, and I04-1 of Diamond Light Source, Didcot, Oxfordshire (UK) for support during data collection (allocations MX11265 and MX15806). Funding: M.D. acknowledges the grant support from the NIH (NS080833 and AI132387) and holds the Investigator in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund. P.S. acknowledges the support by the Swedish Research Council (2014–5667), the Wenner-Gren Foundation, and the Swedish Cancer Society. This study was supported by an industry-sponsored research grant from Ipsen to M.D. and a grant for a postdoctoral fellow to P.S. sponsored by Ipsen.
ASJC Scopus subject areas
- General