De novo designed protein inhibitors of amyloid aggregation and seeding.
De novo designed protein inhibitors of amyloid aggregation and seeding.
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DOI：
10.1073/pnas.2206240119
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发表时间：
2022-08-23
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
我们研究了从头设计的微型蛋白（长度为 35 至 48 个氨基酸残基）在抑制与多种神经退行性疾病相关的蛋白原纤维方面的用途。根据已知的 tau、α-突触核蛋白和β-淀粉样蛋白原纤维的原子结构，我们设计了微型蛋白来覆盖原纤维的生长尖端，阻止进一步生长。我们发现微型蛋白阻止蛋白质聚集成原纤维，并阻止原纤维在其他细胞中诱导或“播种”原纤维生长的能力。抑制其靶蛋白聚集的微型蛋白是特异性的，并且不抑制其他蛋白的聚集。微型蛋白作为最终疗法的一个优点是它们可以被基因编码并可能通过病毒载体递送到患病的大脑。神经退行性疾病的特征是聚集蛋白的病理性积累。这些纤维状聚集体被称为淀粉样蛋白，包括阿尔茨海默病 (AD) 中的 tau 蛋白和淀粉样蛋白-β (Aβ) 以及帕金森病 (PD) 中的 α-突触核蛋白 (αSyn)。淀粉样原纤维在大脑内的发育和扩散与疾病的发病和进展相关，抑制淀粉样蛋白的形成是治疗开发的一种可能途径。最近的进展使得淀粉样原纤维结构的测定达到原子级分辨率，提高了基于结构的抑制剂设计的可能性。在这项工作中，我们利用这些淀粉样蛋白结构来设计与原纤维末端结合的抑制剂，“封盖”它们以防止进一步生长。利用从头蛋白质设计，我们开发了一个包含 35 至 48 个残基的小蛋白抑制剂文库，该文库针对 tau、Aβ 和 αSyn 的淀粉样蛋白结构。计算机设计的顶级抑制剂的生物物理特征表明，它们形成稳定的折叠，与天然存在的蛋白质没有序列相似性，并且在体外专门防止其目标淀粉样蛋白倾向蛋白的聚集。该抑制剂还可以防止细胞中原纤维的种子聚集和毒性。体内评估揭示了它们在 PD 和 AD 秀丽隐杆线虫模型中减少聚集和挽救运动缺陷的能力。
We have investigated the usefulness of de novo designed miniproteins, 35 to 48 amino acid residues in length, for the inhibition of protein fibrils associated with numerous neurodegenerative diseases. From known atomic structures of fibrils of tau, alpha-synuclein, and amyloid-beta, we designed miniproteins to cap the growing tips of fibrils, halting further growth. We find the miniproteins halt protein aggregation into fibrils and halt the ability of fibrils to induce or “seed” fibril growth in other cells. A miniprotein that inhibits aggregation of its target protein is specific and does not inhibit aggregation of other proteins. An advantage of miniproteins as eventual therapeutics is that they can be genetically encoded and possibly delivered to diseased brains by viral vectors. Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-β (Aβ) in Alzheimer’s disease (AD) and alpha-synuclein (αSyn) in Parkinson’s disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, “capping” them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aβ, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD.
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影响因子：
64.8
作者：
Chevalier A;Silva DA;Rocklin GJ;Hicks DR;Vergara R;Murapa P;Bernard SM;Zhang L;Lam KH;Yao G;Bahl CD;Miyashita SI;Goreshnik I;Fuller JT;Koday MT;Jenkins CM;Colvin T;Carter L;Bohn A;Bryan CM;Fernández-Velasco DA;Stewart L;Dong M;Huang X;Jin R;Wilson IA;Fuller DH;Baker D
通讯作者：
Baker D
影响因子：
64.8
作者：
Bhardwaj, Gaurav;Mulligan, Vikram Khipple;Bahl, Christopher D.;Gilmore, Jason M.;Harvey, Peta J.;Cheneval, Olivier;Buchko, Garry W.;Pulavarti, Surya V. S. R. K.;Kaas, Quentin;Eletsky, Alexander;Huang, Po-Ssu;Johnsen, William A.;Greisen, Per Jr;Rocklin, Gabriel J.;Song, Yifan;Linsky, Thomas W.;Watkins, Andrew;Rettie, Stephen A.;Xu, Xianzhong;Carter, Lauren P.;Bonneau, Richard;Olson, James M.;Coutsias, Evangelos;Correnti, Colin E.;Szyperski, Thomas;Craik, David J.;Baker, David
通讯作者：
Baker, David
影响因子：
16.8
作者：
Cao, Qin;Boyer, David R.;Eisenberg, David S.
通讯作者：
Eisenberg, David S.
影响因子：
3.5
作者：
Fatouros, Chronis;Pir, Ghulam Jeelani;Baumeister, Ralf
通讯作者：
Baumeister, Ralf
影响因子：
2.9
作者：
Heldt, Caryn L.;Zhang, Shuqi;Belfort, Georges
通讯作者：
Belfort, Georges