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Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models
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Number of Authors: 192019 (English)In: Science Advances, E-ISSN 2375-2548, Vol. 5, no 1, article id eaau7196Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 5, no 1, article id eaau7196
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Biological Sciences Cell and Molecular Biology
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URN: urn:nbn:se:su:diva-166621DOI: 10.1126/sciadv.aau7196ISI: 000457547900055PubMedID: 30746458OAI: oai:DiVA.org:su-166621DiVA, id: diva2:1297573
Available from: 2019-03-20 Created: 2019-03-20 Last updated: 2019-03-20Bibliographically approved

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Masuyer, GeoffreyStenmark, Pål
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