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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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 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.

Detaljer

Författare
  • Mark Elliott
  • Christine Favre-Guilmard
  • Sai Man Liu
  • Jacquie Maignel
  • Geoffrey Masuyer
  • Matthew Beard
  • Christopher Boone
  • Denis Carré
  • Mikhail Kalinichev
  • Stephane Lezmi
  • Imran Mir
  • Camille Nicoleau
  • Shilpa Palan
  • Cindy Perier
  • Elsa Raban
  • Sicai Zhang
  • Min Dong
  • Pål Stenmark
  • Johannes Krupp
Enheter & grupper
Externa organisationer
  • IPSEN Foundation
  • Stockholms universitet
  • Boston Children's Hospital
  • Harvard University
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Mikrobiologi inom det medicinska området
Originalspråkengelska
Artikelnummereaau7196
TidskriftScience Advances
Volym5
Utgivningsnummer1
StatusPublished - 2019
PublikationskategoriForskning
Peer review utfördJa