Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models

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Bibtex

@article{771ef0768b89430faab106d3a7cb724a,
title = "Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models",
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/B1MY) and E1191Q/S1199W (rBoNT/B1QW) 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/B1MY 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.",
author = "Mark Elliott and Christine Favre-Guilmard and Liu, {Sai Man} and Jacquie Maignel and Geoffrey Masuyer and Matthew Beard and Christopher Boone and Denis Carr{\'e} and Mikhail Kalinichev and Stephane Lezmi and Imran Mir and Camille Nicoleau and Shilpa Palan and Cindy Perier and Elsa Raban and Sicai Zhang and Min Dong and P{\aa}l Stenmark and Johannes Krupp",
year = "2019",
doi = "10.1126/sciadv.aau7196",
language = "English",
volume = "5",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science (AAAS)",
number = "1",

}