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

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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.

I: Science Advances, Vol. 5, Nr. 1, eaau7196, 2019.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

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, nr. 1, eaau7196. https://doi.org/10.1126/sciadv.aau7196

APA

Elliott, M., Favre-Guilmard, C., Liu, S. M., Maignel, J., Masuyer, G., Beard, M., ... Krupp, J. (2019). Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models. Science Advances, 5(1), [eaau7196]. https://doi.org/10.1126/sciadv.aau7196

CBE

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. 5(1). https://doi.org/10.1126/sciadv.aau7196

MLA

Vancouver

Author

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. I: Science Advances. 2019 ; Vol. 5, Nr. 1.

RIS

TY - JOUR

T1 - Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models

AU - Elliott, Mark

AU - Favre-Guilmard, Christine

AU - Liu, Sai Man

AU - Maignel, Jacquie

AU - Masuyer, Geoffrey

AU - Beard, Matthew

AU - Boone, Christopher

AU - Carré, Denis

AU - Kalinichev, Mikhail

AU - Lezmi, Stephane

AU - Mir, Imran

AU - Nicoleau, Camille

AU - Palan, Shilpa

AU - Perier, Cindy

AU - Raban, Elsa

AU - Zhang, Sicai

AU - Dong, Min

AU - Stenmark, Pål

AU - Krupp, Johannes

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1126/sciadv.aau7196

DO - 10.1126/sciadv.aau7196

M3 - Article

VL - 5

JO - Science Advances

T2 - Science Advances

JF - Science Advances

SN - 2375-2548

IS - 1

M1 - eaau7196

ER -