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

被引：30

作者：

Elliott, Mark ^{[1
]}

Favre-Guilmard, Christine ^{[2
]}

Liu, Sai Man ^{[1
]}

Maignel, Jacquie ^{[2
]}

Masuyer, Geoffrey ^{[3
]}

Beard, Matthew ^{[1
]}

Boone, Christopher ^{[4
,5
]}

Carre, Denis ^{[2
]}

Kalinichev, Mikhail ^{[2
]}

Lezmi, Stephane ^{[2
]}

Mir, Imran ^{[1
]}

Nicoleau, Camille ^{[2
]}

Palan, Shilpa ^{[1
]}

Perier, Cindy ^{[2
]}

Raban, Elsa ^{[2
]}

Zhang, Sicai ^{[4
,5
]}

Dong, Min ^{[4
,5
]}

Stenmark, Pal ^{[3
,6
]}

Krupp, Johannes ^{[1
,2
]}

机构：

[1] Ipsen Bioinnovat, 102 Pk Dr,Milton Pk, Abingdon OX14 4RY, Oxon, England

[2] Ipsen Bioinnovat, 5 Ave Canada, F-91940 Les Ulis, France

[3] Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden

[4] Harvard Med Sch, Boston Childrens Hosp, Dept Microbiol & Immunobiol, Dept Urol, Boston, MA 02115 USA

[5] Harvard Med Sch, Dept Surg, Boston, MA 02115 USA

[6] Lund Univ, Dept Expt Med Sci, S-22100 Lund, Sweden

来源：

SCIENCE ADVANCES | 2019年 / 5卷 / 01期

基金：

瑞典研究理事会;

关键词：

NEUROTRANSMITTER RELEASE; SYNAPTOTAGMIN-II; PROTEIN-RECEPTOR; HIGH-AFFINITY; SEROTYPE-A; IMPAIRMENT; THERAPY; NEURONS;

D O I：

10.1126/sciadv.aau7196

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

共 25 条

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