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Sci Adv. 2019 Jan 16;5(1):eaau7196. doi: 10.1126/sciadv.aau7196. eCollection 2019 Jan.

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

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Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon OX14 4RY, UK.
Ipsen Innovation, 5 Avenue du Canada, 91940 Les Ulis, France.
Department of Biochemistry and Biophysics, Stockholm University, Stockholm SE-106 91, Sweden.
Department of Urology, Boston Children's Hospital, Department of Microbiology and Immunobiology and Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
Department of Experimental Medical Science, Lund University, 221 00 Lund, Sweden.


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.

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