8FQ7

Nanobody with WIW inserted in CDR3 loop to Inhibit Growth of Alzheimer's Tau fibrils

8FQ7 の概要

• エントリーDOI: 10.2210/pdb8fq7/pdb
• 分子名称: Nanobody with WIW insert in CDR3 loop to target tau fibrils, GLYCEROL (3 entities in total)
• 機能のキーワード: anti-tau antibody, nanobody, immune system
• 由来する生物種: Camelus dromedarius
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13860.28

構造登録者

Abskharon, R.,Sawaya, M.R.,Cascio, D.C.,Eisenberg, D.S. (登録日: 2023-01-05, 公開日: 2023-10-04, 最終更新日: 2024-10-30)

主引用文献

Abskharon, R.,Pan, H.,Sawaya, M.R.,Seidler, P.M.,Olivares, E.J.,Chen, Y.,Murray, K.A.,Zhang, J.,Lantz, C.,Bentzel, M.,Boyer, D.R.,Cascio, D.,Nguyen, B.A.,Hou, K.,Cheng, X.,Pardon, E.,Williams, C.K.,Nana, A.L.,Vinters, H.V.,Spina, S.,Grinberg, L.T.,Seeley, W.W.,Steyaert, J.,Glabe, C.G.,Ogorzalek Loo, R.R.,Loo, J.A.,Eisenberg, D.S.
Structure-based design of nanobodies that inhibit seeding of Alzheimer's patient-extracted tau fibrils.
Proc.Natl.Acad.Sci.USA, 120:e2300258120-e2300258120, 2023

PubMed Abstract: Despite much effort, antibody therapies for Alzheimer's disease (AD) have shown limited efficacy. Challenges to the rational design of effective antibodies include the difficulty of achieving specific affinity to critical targets, poor expression, and antibody aggregation caused by buried charges and unstructured loops. To overcome these challenges, we grafted previously determined sequences of fibril-capping amyloid inhibitors onto a camel heavy chain antibody scaffold. These sequences were designed to cap fibrils of tau, known to form the neurofibrillary tangles of AD, thereby preventing fibril elongation. The nanobodies grafted with capping inhibitors blocked tau aggregation in biosensor cells seeded with postmortem brain extracts from AD and progressive supranuclear palsy (PSP) patients. The tau capping nanobody inhibitors also blocked seeding by recombinant tau oligomers. Another challenge to the design of effective antibodies is their poor blood-brain barrier (BBB) penetration. In this study, we also designed a bispecific nanobody composed of a nanobody that targets a receptor on the BBB and a tau capping nanobody inhibitor, conjoined by a flexible linker. We provide evidence that the bispecific nanobody improved BBB penetration over the tau capping inhibitor alone after intravenous administration in mice. Our results suggest that the design of synthetic antibodies that target sequences that drive protein aggregation may be a promising approach to inhibit the prion-like seeding of tau and other proteins involved in AD and related proteinopathies.

PubMed: 37801475
DOI: 10.1073/pnas.2300258120

実験手法

X-RAY DIFFRACTION (1.4 Å)