The structural basis for optimal performance of oligothiophene-based fluorescent amyloid ligands: conformational flexibility is essential for spectral assignment of a diversity of protein aggregates.
The structural basis for optimal performance of oligothiophene-based fluorescent amyloid ligands: conformational flexibility is essential for spectral assignment of a diversity of protein aggregates.
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DOI：
10.1002/chem.201301463
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发表时间：
2013-07-29
影响因子：
4.3
通讯作者：
Nilsson, K. Peter R.
中科院分区：
文献类型：
--
作者：
Klingstedt, Therese;Shirani, Hamid;Aslund, K. O. Andreas;Cairns, Nigel J.;Sigurdson, Christina J.;Goedert, Michel;Nilsson, K. Peter R.
关键词：
蛋白质错误折叠疾病的特征在于蛋白质聚集体的沉积，并且用于这些疾病相关结构的分子表征的光学配体对于理解它们在疾病的发病机制中的潜在作用是重要的。发光共轭低聚噻吩（LCO）已被证明可用于比常规配体（如硫磺素T和刚果红）更广泛的疾病相关蛋白聚集体子集的光学鉴定。 在此，研究了实现能够检测非嗜硫黄素Aβ聚集体或非嗜硫朊病毒聚集体以及光谱区分Aβ和tau聚集体的LCO的分子要求。阴离子五聚体LCO通过以下进行化学工程：1）用硒代或亚苯基部分取代噻吩单元，或2）使阴离子取代基沿着噻吩主链交替。 此外，生成了两个不对称四聚体配体。总体而言，本研究的结果确定了共轭骨架的构象自由度和扩展共轭是获得上级噻吩基光学配体的关键决定因素，用于疾病相关蛋白质聚集体的灵敏检测和光谱分配。
Protein misfolding diseases are characterized by deposition of protein aggregates, and optical ligands for molecular characterization of these disease-associated structures are important for understanding their potential role in the pathogenesis of the disease. Luminescent conjugated oligothiophenes (LCOs) have proven useful for optical identification of a broader subset of disease-associated protein aggregates than conventional ligands, such as thioflavin T and Congo red. Herein, the molecular requirements for achieving LCOs able to detect nonthioflavinophilic Aβ aggregates or non-congophilic prion aggregates, as well as spectrally discriminate Aβ and tau aggregates, were investigated. An anionic pentameric LCO was subjected to chemical engineering by: 1) replacing thiophene units with selenophene or phenylene moieties, or 2) alternating the anionic substituents along the thiophene backbone. In addition, two asymmetric tetrameric ligands were generated. Overall, the results from this study identified conformational freedom and extended conjugation of the conjugated backbone as crucial determinants for obtaining superior thiophene-based optical ligands for sensitive detection and spectral assignment of disease-associated protein aggregates.
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影响因子：
3.2
作者：
Klingstedt T;Aslund A;Simon RA;Johansson LB;Mason JJ;Nyström S;Hammarström P;Nilsson KP
通讯作者：
Nilsson KP
影响因子：
8.6
作者：
Haid, Stefan;Mishra, Amaresh;Baeuerle, Peter
通讯作者：
Baeuerle, Peter
影响因子：
3.2
作者：
Dal Molin, Marta;Matile, Stefan
通讯作者：
Matile, Stefan
影响因子：
4
作者：
Aslund, Andreas;Sigurdson, Christina J.;Klingstedt, Therese;Grathwohl, Stefan;Bolmont, Tristan;Dickstein, Dara L.;Glimsdal, Eirik;Prokop, Stefan;Lindgren, Mikael;Konradsson, Peter;Holtzman, David M.;Hof, Patrick R.;Heppner, Frank L.;Gandy, Samuel;Jucker, Mathias;Aguzzi, Adriano;Hammarstrom, Per;Nilsson, K. Peter R.
通讯作者：
Nilsson, K. Peter R.
影响因子：
3.2
作者：
Klingstedt, Therse;Blechschmidt, Cristiane;Nogalska, Anna;Prokop, Stefan;Haggqvist, Bo;Danielsson, Olof;Engel, W. King;Askanas, Valerie;Heppner, Frank L.;Nilsson, K. Peter R.
通讯作者：
Nilsson, K. Peter R.