Engineered botulinum neurotoxin B with improved efficacy for targeting human receptors

Liang Tao, Lisheng Peng, Ronnie P.-A. Berntsson, Sai Man Liu, SunHyun Park, Feifan Yu, Christopher Boone, Shilpa Palan, Matthew Beard, Pierre-Etienne Chabrier, Pål Stenmark (), Johannes Krupp () and Min Dong ()
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Liang Tao: Harvard Medical School
Lisheng Peng: Harvard Medical School
Ronnie P.-A. Berntsson: Stockholm University
Sai Man Liu: IPSEN Bioinnovation
SunHyun Park: Harvard Medical School
Feifan Yu: Harvard Medical School
Christopher Boone: Harvard Medical School
Shilpa Palan: IPSEN Bioinnovation
Matthew Beard: IPSEN Bioinnovation
Pierre-Etienne Chabrier: IPSEN Innovation
Pål Stenmark: Stockholm University
Johannes Krupp: IPSEN Bioinnovation
Min Dong: Harvard Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Botulinum neurotoxin B is a Food and Drug Administration-approved therapeutic toxin. However, it has lower binding affinity toward the human version of its major receptor, synaptotagmin II (h-Syt II), compared to mouse Syt II, because of a residue difference. Increasing the binding affinity to h-Syt II may improve botulinum neurotoxin B’s therapeutic efficacy and reduce adverse effects. Here we utilized the bacterial adenylate cyclase two-hybrid method and carried out a saturation mutagenesis screen in the Syt II-binding pocket of botulinum neurotoxin B. The screen identifies E1191 as a key residue: replacing it with M/C/V/Q enhances botulinum neurotoxin B binding to human synaptotagmin II. Adding S1199Y/W or W1178Q as a secondary mutation further increases binding affinity. Mutant botulinum neurotoxin B containing E1191M/S1199Y exhibits ~11-fold higher efficacy in blocking neurotransmission than wild-type botulinum neurotoxin B in neurons expressing human synaptotagmin II, demonstrating that enhancing receptor binding increases the overall efficacy at functional levels. The engineered botulinum neurotoxin B provides a platform to develop therapeutic toxins with improved efficacy.

Date: 2017
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DOI: 10.1038/s41467-017-00064-y

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