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Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models
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 expr...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for the Advancement of Science
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357751/ https://www.ncbi.nlm.nih.gov/pubmed/30746458 http://dx.doi.org/10.1126/sciadv.aau7196 |
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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 |
author_facet | 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 |
author_sort | Elliott, Mark |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6357751 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-63577512019-02-11 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 Sci Adv Research Articles 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. American Association for the Advancement of Science 2019-01-16 /pmc/articles/PMC6357751/ /pubmed/30746458 http://dx.doi.org/10.1126/sciadv.aau7196 Text en Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles 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 |
title | Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models |
title_full | Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models |
title_fullStr | Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models |
title_full_unstemmed | Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models |
title_short | Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models |
title_sort | engineered botulinum neurotoxin b with improved binding to human receptors has enhanced efficacy in preclinical models |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357751/ https://www.ncbi.nlm.nih.gov/pubmed/30746458 http://dx.doi.org/10.1126/sciadv.aau7196 |
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