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

Elliott, Mark A.; Favre-Guilmard, Christine; Liu, Sai Man; Maignel, Jacquie; Masuyer, Geoffrey; Beard, Matthew; Boone, Christopher D.; Carré, Denis; Kalinichev, Mikhail; Lezmi, Stéphane; Mir, Imran; Nicoleau, Camille; Palan, Shilpa; Périer, Cindy; Raban, Elsa; Zhang, Sicai; Dong, Min; Stenmark, Pål; Krupp, Johannes

doi:10.1126/sciadv.aau7196

Cited by 33 publications

(51 citation statements)

References 46 publications

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“…This is consistent with clinical observations suggesting that BoNT/B may have advantages over BoNT/A in treating disorders involving smooth muscles and the autonomic nervous system [60,63]. Thus, BoNT/B MY may offer a higher therapeutic efficacy than BoNT/A for treating smooth muscle-related disorders [62].…”

Section: Introductionsupporting

confidence: 89%

“…Interestingly, BoNT/B and BoNT/B MY showed a higher potency than BoNT/A in paralyzing bladder muscles, which are smooth muscles [62]. This is consistent with clinical observations suggesting that BoNT/B may have advantages over BoNT/A in treating disorders involving smooth muscles and the autonomic nervous system [60,63].…”

Section: Introductionsupporting

confidence: 85%

“…This led to the creation of a mutant BoNT/B (e.g., BoNT/B MY ) that can bind to human Syt II with high affinity. Whereas wild-type (WT) BoNT/B showed lower efficacy than BoNT/A in a humanized mouse model in which the Syt II luminal domain has been replaced with the human version, BoNT/B MY and BoNT/A showed similar efficacy in paralyzing skeletal muscles in this humanized mouse model [62].…”

Section: Introductionmentioning

confidence: 90%

“…cDNA encoding mouse Syt II 1-267 was subcloned into the pET28a vector and expressed as an N-terminal His6-tagged protein. cDNA encoding BoNT/B MY was subcloned into pET32a as previously described [62]. A stop codon was introduced to remove the C-terminal His6-tag.…”

Section: Constructs and Protein Purificationsmentioning

confidence: 99%

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Characterization of a membrane binding loop leads to engineering botulinum neurotoxin B with improved therapeutic efficacy

et al. 2020

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Section: Introductionsupporting

confidence: 89%

Section: Introductionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 90%

Section: Constructs and Protein Purificationsmentioning

confidence: 99%

See 2 more Smart Citations

Characterization of a membrane binding loop leads to engineering botulinum neurotoxin B with improved therapeutic efficacy

et al. 2020

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“…Although there are minor sequence differences between SYT1 and SYT2 N-terminal domains, the affinity of BoNT/B for rat SYT2 is more than 2 orders of magnitude higher than for rat SYT1 (16). Interestingly, however, a single amino acid difference between rat and human SYT2 drastically diminishes BoNT/B binding affinity for the latter and consequently SYT1 is considered to be the major receptor for BoNT/B in humans at NMJ (17) and autonomic nerve terminals (18). X-ray crystallography has shown that the trefoil C-terminal domain of BoNT/B carries 2 vicinal but independent binding pockets.…”

Section: Significancementioning

confidence: 98%

Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B

Flores

Ramírez‐Franco

Desplantes

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Botulinum neurotoxin type B (BoNT/B) recognizes nerve terminals by binding to 2 receptor components: a polysialoganglioside, predominantly GT1b, and synaptotagmin 1/2. It is widely thought that BoNT/B initially binds to GT1b then diffuses in the plane of the membrane to interact with synaptotagmin. We have addressed the hypothesis that a GT1b–synaptotagmin cis complex forms the BoNT/B receptor. We identified a consensus glycosphingolipid-binding motif in the extracellular juxtamembrane domain of synaptotagmins 1/2 and confirmed by Langmuir monolayer, surface plasmon resonance, and circular dichroism that GT1b interacts with synaptotagmin peptides containing this sequence, inducing α-helical structure. Molecular modeling and tryptophan fluorescence spectroscopy were consistent with the intertwining of GT1b and synaptotagmin, involving cis interactions between the oligosaccharide and ceramide moieties of GT1b and the juxtamembrane and transmembrane domains of synaptotagmin, respectively. Furthermore, a point mutation on synaptotagmin, located outside of the BoNT/B-binding segment, inhibited GT1b binding and blocked GT1b-induced potentiation of BoNT/B binding to synaptotagmin-expressing cells. Our findings are consistent with a model in which a preassembled GT1b–synaptotagmin complex constitutes the high-affinity BoNT/B receptor.

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4D Oriented Dynamic Scaffold for Promoting Peripheral Nerve Regeneration and Functional Recovery

Sun,

You,

Zhan

et al. 2023

Adv Funct Materials

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Neurological function recovery after peripheral nerve injury (PNI) is exceptionally challenging, chiefly because neurons cannot efficiently proliferate, differentiate, and form regenerated axons to pass through the defect region expeditiously and transmit neurological signals. In this study, a four‐dimensional (4D) oriented dynamic scaffold is constructed based on shape memory polymer (SMP), which can regulate spatiotemporally controllable neuronal early adequate proliferation, subsequently effective differentiation and axon formation by synergizing the on‐demand microtopography and deformation force‐based mechanical stimuli (DFMS). This dynamic scaffold can accelerate the restoration of large segmental nerve defects, elevate the neural signaling efficiency by 60% compared with static scaffold, and finally form the functionalized robust regenerating nerve fascicles with comparable therapeutic effects on autologous nerve transplantation. Furthermore, the crucial role of Piezo1/Camk2b modulated neuronal differentiation and axon extension is also revealed through deep transcriptomic analysis. In summary, the 4D oriented dynamic scaffold can precisely and remotely regulate neuronal behavior and fate in a non‐invasive way, which has excellent potential for clinical application in peripheral nerve restoration.

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

Abstract: We report the preclinical characterization of two engineered botulinum neurotoxin serotype B proteins with significant therapeutic potential.

Cited by 33 publications

References 46 publications

Characterization of a membrane binding loop leads to engineering botulinum neurotoxin B with improved therapeutic efficacy

Characterization of a membrane binding loop leads to engineering botulinum neurotoxin B with improved therapeutic efficacy

Gangliosides interact with synaptotagmin to form the high-affinity receptor complex for botulinum neurotoxin B

4D Oriented Dynamic Scaffold for Promoting Peripheral Nerve Regeneration and Functional Recovery

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