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Study of A
β Aggregation Inhibitors Based on Multiple Weak Interactions- Acta Polymerica Sinica Vol. 0, Issue 7, Pages: 776-785(2018)
- 作者机构：
1.功能高分子材料教育部重点实验室 南开大学化学学院 天津 300071
2.天津化学化工协同创新中心 天津 300071
- 作者简介：
- 基金信息：
DOI：10.11777/j.issn1000-3304.2018.18025
CLC：Published：2018-7，
Received：21 January 2018，
Revised：17 April 2018，
扫 描 看 全 文
Qian Zhang, Zhi Yuan. Study of A
β Aggregation Inhibitors Based on Multiple Weak Interactions. [J]. Acta Polymerica Sinica 0(7):776-785(2018)Qian Zhang, Zhi Yuan. Study of A
β Aggregation Inhibitors Based on Multiple Weak Interactions. [J]. Acta Polymerica Sinica 0(7):776-785(2018) DOI： 10.11777/j.issn1000-3304.2018.18025.
摘要
阿尔茨海默症(Alzheimer’s disease
AD)是一种神经退行性疾病，是老年痴呆最常见的一种形式，它具有不可治愈性、进行性以及致命性. 目前对AD发病机制尚无定论，但普遍认为AD的发生与脑中
β
淀粉样肽(amyloid
β
，A
β
)的聚集累积以及由金属离子富集导致的氧化应激效应有关. 在我们的工作中，首先通过拓展A
β
识别片段，利用多重弱相互作用，采用计算机模拟设计并筛选出新型A
β
聚集抑制肽(RR)，该抑制肽具有高效、低毒以及无自聚等优点；之后，在RR中引入具有Cu离子螯合能力的GGH寡肽片段，使之同时具有抑制A
β
聚集以及活氧物质(ROS)生成的能力. 通过解聚A
β
或A
β
-Cu复合物成熟纤维，可促进脑内A
β
聚集体的细胞胞吞清除，有可能达到治疗AD的效果，并在体内外实验中进行了验证. 综上我们认为，计算机模拟法是一种更高效准确地筛选药物分子的方式，而利用多重弱相互作用设计A
β
聚集抑制剂是行之有效的，该方法不仅适用于AD相关疾病的研究，也可为其他蛋白质及多肽相关疾病提供一种新的研究思路.
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with the loss of memory
cognitive decline
and behavioral disability
leading to dementia and death ultimately. The pathogenesis of AD is still unclear
but it is generally accepted that the occurrence of AD is related to the accumulation of amyloid
β
(A
β
) in the brain and the oxidative stress effect caused by the enrichment of metal ions. In our previous work
we expanded the targeting site from A
β
16-22 to A
β
11-23 (EVHHQKLVFFAED)
which could offer multiple weak interaction sites
such as the electrostatic
hydrophobic interactions and hydrogen bonding. We designed and screened a novel A
β
aggregation inhibitory peptide (RR) by computer simulation. The tripeptide chelator GGH
selected by ITC experiment with selectively Cu ion chelating ability
was introduced into RR to get the bifunctional peptide inhibitor GR
which have the ability to inhibit A
β
aggregation and produce the oxygen species (ROS) production at the same time. The results of ThT fluorescence
turbidity analysis
MTT methods showed that GR can inhibit the aggregation of A
β
and A
β
-Cu complex (A
β
:Cu = 1:0.25) to form amorphous aggregates
and the cell survival of GR group can reach 88%
significantly higher than chelator GGH (49%) and single functional inhibitor RR (68%). Moreover
it is proposed for the first time that the endocytosis of A
β
aggregates in the brain could be promoted by the disaggregation of A
β
or A
β
-Cu complex fibrils to achieve the effect of treating AD. The results showed that RR and GR can disaggregate A
β
and A
β
-Cu complex fibrils to nanorod-like structure with a length of 200 − 250 nm (rA
β
)
and
β
-sheet structure content in the system was reduced by 45%. rA
β
more easily to PC12 cell endocytosis
and it can enter the cells and further into the cell lysosomes. The
in vitro
lysosomal cathepsin B (CatB) degradation experimental results showed that
compared to fA
β
rA
β
is more susceptible to CatB degradation
and its degradation products have no longer full hydrophobic core region
thereby greatly reducing their chances of re-aggregation. Finally the feasibility of GR and RR has been verified in Morris water maze test.
关键词
阿尔茨海默症β淀粉样肽抑制剂
Keywords
Alzheimer’s diseaseAmyloid βPeptide inhibitor
references
Lorenzo A, Yankner B A . Proc Nat Acad Sci USA , . 1994 . 91 ( 25 ): 12243 - 12247.
Kayed R, Head E, Thompson J L, McIntire T M, Milton S C, Cotman C W, Glabe C G . Science , . 2003 . 300 ( 5618 ): 486 - 489.
Keliényi G J . Histochem Cytochem , . 1967 . 15 ( 3 ): 172 - 180.
Vasser P, Culling C . Arch Pathol , . 1959 . 68 487 - 498.
Ono K, Hasegawa K, Naiki H, Yamada M . J Neurosci Res , . 2004 . 75 ( 6 ): 742 - 750.
Yang F, Lim G P, Begum A N, Ubeda O J, Simmons M R, Ambegaokar S S, Chen P P, Kayed R, Glabe C G, Frautschy S A, Cole G M . J Biol Chem , . 2005 . 280 ( 7 ): 5892 - 5901.
Ehrnhoefer D E, Bieschke J, Boeddrich A, Herbst M, Masino L, Lurz R, Engemann S, Pastore A, Wanker E E . Nat Struct Mol Biol , . 2008 . 15 ( 6 ): 558 - 566.
Lührs T, Ritter C, Adrian M, Riek-Loher D, Bohrmann B, Döbeli H, Schubert D, Riek R . Proc Nat Acad Sci UAS , . 2005 . 102 ( 48 ): 17342 - 17347.
Tjernberg L O, Näslund J, Lindqvist F, Johansson J, Karlström A R, Thyberg J, Terenius L, Nordsteddt C . J Biol Chem , . 1996 . 271 ( 15 ): 8545 - 8548.
Soto C, Sigurdsson E M, Morelli L, Kumar R A, Castaño E M, Frangione B . Nat Med , . 1998 . 4 ( 7 ): 822 - 826.
Hetényi C, Szabó Z, Klement É, Datki Z, Körtvélyesi T, Zarándi M, Penke B . Biochem Biophys Res Commun , . 2002 . 292 ( 4 ): 931 - 936.
Kogan M J, Bastus N G, Amigo R, Grillo-Bosch D, Araya E, Turiel A, Labarta A, Puntes V F . Nano Lett , . 2006 . 6 ( 1 ): 110 - 115.
Viet M H, Ngo S T, Lam N S, Li M S . J Phys Chem B , . 2011 . 115 ( 22 ): 7433 - 7446.
Liu J, Wang W, Zhang Q, Zhang S, Yuan Z . Biomacromolecules , . 2014 . 15 ( 3 ): 931 - 939.
Liu J, Yuan Z . Chinese J Polym Sci , . 2015 . 33 ( 7 ): 1009 - 1017.
Levine H . Protein Sci , . 1993 . 2 ( 3 ): 404 - 410.
Necula M, Kayed R, Milton S, Glabe C G . J Biol Chem , . 2007 . 282 ( 14 ): 10311 - 10324.
Kepp K P . Chem Rev , . 2012 . 112 ( 10 ): 5193 - 5239.
Faller P, Hureau C, Berthoumieu O . Inorg Chem , . 2013 . 52 ( 21 ): 12193 - 12206.
Hureau C . Coord Chem Rev , . 2012 . 256 ( 19-20 ): 2164 - 2174.
Bush A I . Neurobio Ag , . 2002 . 23 1031 - 1038.
Adlard P A, Cherny R A, Finkelstein D I, Gautier E, Robb E, Cortes M, Volitakis I, Liu X, Smith J P, Perez K, Laughton K, Li Q X, Charman S A, Nicolazzo J A, Wilkins S, Deleva K, Lynch T, Kok G, Ritchie C W, Tanzi R E, Cappai R, Masters C L, Barnham K J, Bush A I . Neuron , . 2008 . 59 ( 1 ): 43 - 55.
Geng J, Li M, Wu L, Chen C, Qu X . Adv Healthcare Mater , . 2012 . 1 ( 3 ): 332 - 336.
Li M, Xu C, Ren J, Wang E, Qu X . Chem Commun , . 2013 . 49 ( 97 ): 11394 - 11396.
Jensen M, Canning A, Chiha S, Bouquerel P, Pedersen J T, Jesper Østergaard, Olivier Cuvillier, Sasaki S, Hureau C, Faller P . Chem Eur J , . 2012 . 18 ( 16 ): 4836 - 4839.
Zhang Q, Hu X, Wang W, Yuan Z . Biomacromolecules , . 2016 . 17 ( 2 ): 661 - 668.
Hu X, Zhang Q, Wang W, Yuan Z, Zhu X, Chen B, Chen X . ACS Chem Neurosci , . 2016 . 7 ( 9 ): 1255 - 1263.
Bateman R J, Munsell L Y, Morris J C, Swarm R, Yarasheski K E, Holtzman D M . Nat Med , . 2006 . 12 ( 7 ): 856 - 861.
Mawuenyega K G, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris J C, Yarasheski K E, Bateman R J . Science , . 2010 . 330 ( 6012 ): 1774 .
Zhang Q, Liu J, Hu X, Wang W, Yuan Z . ACS Macro Lett , . 2015 . 4 ( 4 ): 339 - 342.
Wang D, Zhang Q, Hu X, Wang W, Zhu X, Yuan Z . Acta Biomaterialia , . 2018 . 65 327 - 338.
Morris R G M, Garrud P, Rawlins J N P, O’Keefe J . Nature , . 1982 . 297 ( 5868 ): 681 - 683.
Song Q, Huang M, Yao L, Wang X, Gu X, Chen J, Chen J, Huang J, Hu Q, Kang T . ACS Nano , . 2014 . 8 ( 3 ): 2345 - 2359.
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