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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2019
Materias:
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
Descripción
Sumario: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.