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结构洞察：基于单域抗体的肉毒神经毒素解毒剂的理性设计

Structural Insights into Rational Design of Single-Domain Antibody-Based Antitoxins against Botulinum Neurotoxins.

机构信息

Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, USA.

Tufts Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.

出版信息

Cell Rep. 2020 Feb 25;30(8):2526-2539.e6. doi: 10.1016/j.celrep.2020.01.107.

DOI:10.1016/j.celrep.2020.01.107
PMID:32101733
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7138525/
Abstract

Botulinum neurotoxin (BoNT) is one of the most acutely lethal toxins known to humans, and effective treatment for BoNT intoxication is urgently needed. Single-domain antibodies (VHH) have been examined as a countermeasure for BoNT because of their high stability and ease of production. Here, we investigate the structures and the neutralization mechanisms for six unique VHHs targeting BoNT/A1 or BoNT/B1. These studies reveal diverse neutralizing mechanisms by which VHHs prevent host receptor binding or block transmembrane delivery of the BoNT protease domain. Guided by this knowledge, we design heterodimeric VHHs by connecting two neutralizing VHHs via a flexible spacer so they can bind simultaneously to the toxin. These bifunctional VHHs display much greater potency in a mouse co-intoxication model than similar heterodimers unable to bind simultaneously. Taken together, our studies offer insight into antibody neutralization of BoNTs and advance our ability to design multivalent anti-pathogen VHHs with improved therapeutic properties.

摘要

肉毒毒素（BoNT）是已知对人类最具致命性的毒素之一，因此急需有效的 BoNT 中毒治疗方法。由于单域抗体（VHH）具有高稳定性和易于生产的特点，因此被研究作为 BoNT 的应对措施。在这里，我们研究了针对 BoNT/A1 或 BoNT/B1 的六种独特 VHH 的结构和中和机制。这些研究揭示了 VHH 通过阻止宿主受体结合或阻断 BoNT 蛋白酶结构域的跨膜递送来预防中和的多种机制。基于这些知识，我们通过连接两个中和 VHH 来设计异二聚体 VHH 通过一个柔性间隔物，以便它们可以同时与毒素结合。这些双功能 VHH 在小鼠共同中毒模型中的效力比不能同时结合的类似异二聚体高得多。总之，我们的研究深入了解了 BoNT 的抗体中和作用，并提高了我们设计具有改进治疗特性的多价抗病原体 VHH 的能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/d99a07a6b43f/nihms-1566843-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/fb2851692830/nihms-1566843-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/f78129d4bb63/nihms-1566843-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/e3ff546c8860/nihms-1566843-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/f9ec9f298b60/nihms-1566843-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/23fb44f15918/nihms-1566843-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/a916b555a542/nihms-1566843-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/d99a07a6b43f/nihms-1566843-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/fb2851692830/nihms-1566843-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/f78129d4bb63/nihms-1566843-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/e3ff546c8860/nihms-1566843-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/f9ec9f298b60/nihms-1566843-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/23fb44f15918/nihms-1566843-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/a916b555a542/nihms-1566843-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ab79/7138525/d99a07a6b43f/nihms-1566843-f0008.jpg

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