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

Mark Elliott, Christine Favre-Guilmard, Sai Man Liu, Jacquie Maignel, Geoffrey Masuyer, Matthew Beard, Christopher Boone, Denis Carré, Mikhail Kalinichev, Stephane Lezmi, Imran Mir, Camille Nicoleau, Shilpa Palan, Cindy Perier, Elsa Raban, Sicai Zhang, Min Dong, Pål Stenmark, Johannes Krupp

Research output: Contribution to journalArticle

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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 languageEnglish
Article numbereaau7196
Pages (from-to)1-13
Number of pages13
JournalScience Advances
Volume5
Issue number1
DOIs
Publication statusPublished - 16 Jan 2019

ASJC Scopus subject areas

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Cite this

Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models. / Elliott, Mark; Favre-Guilmard, Christine; Liu, Sai Man; Maignel, Jacquie; Masuyer, Geoffrey; Beard, Matthew; Boone, Christopher; Carré, Denis; Kalinichev, Mikhail; Lezmi, Stephane; Mir, Imran; Nicoleau, Camille; Palan, Shilpa; Perier, Cindy; Raban, Elsa; Zhang, Sicai; Dong, Min; Stenmark, Pål; Krupp, Johannes.

In: Science Advances, Vol. 5, No. 1, eaau7196, 16.01.2019, p. 1-13.

Research output: Contribution to journalArticle

Elliott, M, Favre-Guilmard, C, Liu, SM, Maignel, J, Masuyer, G, Beard, M, Boone, C, Carré, D, Kalinichev, M, Lezmi, S, Mir, I, Nicoleau, C, Palan, S, Perier, C, Raban, E, Zhang, S, Dong, M, Stenmark, P & Krupp, J 2019, 'Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models', Science Advances, vol. 5, no. 1, eaau7196, pp. 1-13. https://doi.org/10.1126/sciadv.aau7196
Elliott, Mark ; Favre-Guilmard, Christine ; Liu, Sai Man ; Maignel, Jacquie ; Masuyer, Geoffrey ; Beard, Matthew ; Boone, Christopher ; Carré, Denis ; Kalinichev, Mikhail ; Lezmi, Stephane ; Mir, Imran ; Nicoleau, Camille ; Palan, Shilpa ; Perier, Cindy ; Raban, Elsa ; Zhang, Sicai ; Dong, Min ; Stenmark, Pål ; Krupp, Johannes. / Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models. In: Science Advances. 2019 ; Vol. 5, No. 1. pp. 1-13.
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