Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models
(2019) In Science Advances 5(1).- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Science Advances
- volume
- 5
- issue
- 1
- article number
- eaau7196
- publisher
- American Association for the Advancement of Science (AAAS)
- external identifiers
-
- scopus:85060037659
- pmid:30746458
- ISSN
- 2375-2548
- DOI
- 10.1126/sciadv.aau7196
- language
- English
- LU publication?
- yes
- id
- 771ef076-8b89-430f-aab1-06d3a7cb724a
- date added to LUP
- 2019-01-29 08:07:36
- date last changed
- 2024-07-10 07:20:45
@article{771ef076-8b89-430f-aab1-06d3a7cb724a, abstract = {{<p>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<sub>MY</sub>) and E1191Q/S1199W (rBoNT/B1<sub>QW</sub>) 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<sub>MY</sub> 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.</p>}}, author = {{Elliott, Mark and Favre-Guilmard, Christine and Liu, Sai Man and Maignel, Jacquie and Masuyer, Geoffrey and Beard, Matthew and Boone, Christopher and Carré, Denis and Kalinichev, Mikhail and Lezmi, Stephane and Mir, Imran and Nicoleau, Camille and Palan, Shilpa and Perier, Cindy and Raban, Elsa and Zhang, Sicai and Dong, Min and Stenmark, Pål and Krupp, Johannes}}, issn = {{2375-2548}}, language = {{eng}}, number = {{1}}, publisher = {{American Association for the Advancement of Science (AAAS)}}, series = {{Science Advances}}, title = {{Engineered botulinum neurotoxin B with improved binding to human receptors has enhanced efficacy in preclinical models}}, url = {{http://dx.doi.org/10.1126/sciadv.aau7196}}, doi = {{10.1126/sciadv.aau7196}}, volume = {{5}}, year = {{2019}}, }