Chiral LVFFARK enantioselectively inhibits amyloid-β protein fibrillogenesis

doi:10.1016/j.cjche.2021.05.033

中国化学工程学报 ›› 2022, Vol. 48 ›› Issue (8): 227-235.DOI: 10.1016/j.cjche.2021.05.033

Chiral LVFFARK enantioselectively inhibits amyloid-β protein fibrillogenesis

Wei Liu, Xueting Sun, Xiaoyan Dong, Yan Sun

Department of Biochemical Engineering, School of Chemical Engineering and Technology and Key Laboratory of Systems Bioengineering and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300350, China

收稿日期:2021-04-12 修回日期:2021-05-19 出版日期:2022-08-28 发布日期:2022-09-30
通讯作者: Yan Sun,E-mail:ysun@tju.edu.cn
基金资助:
This work was supported by the National Natural Science Foundation of China (Nos. 21621004 and 21978207) and the Natural Science Foundation of Tianjin from Tianjin Municipal Science and Technology Commission (No. 19JCZDJC36800).

Chiral LVFFARK enantioselectively inhibits amyloid-β protein fibrillogenesis

Wei Liu, Xueting Sun, Xiaoyan Dong, Yan Sun

Department of Biochemical Engineering, School of Chemical Engineering and Technology and Key Laboratory of Systems Bioengineering and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300350, China

Received:2021-04-12 Revised:2021-05-19 Online:2022-08-28 Published:2022-09-30
Contact: Yan Sun,E-mail:ysun@tju.edu.cn
Supported by:
This work was supported by the National Natural Science Foundation of China (Nos. 21621004 and 21978207) and the Natural Science Foundation of Tianjin from Tianjin Municipal Science and Technology Commission (No. 19JCZDJC36800).

摘要/Abstract

摘要： The modulation of protein aggregation is involved not only in biochemical engineering processes, but also in in vivo biological events such as Alzheimer’s disease (AD) that features amyloid-β protein (Aβ) deposits. Inspired by the different pharmacological efficacy of enantiomers, taking heptapeptide LVFFARK (LK7) as an example, herein the chiral influence of peptide inhibitors on Aβ fibrillogenesis and cytotoxicity was investigated by extensive biophysical and biological analyses. It was intriguing to find that although both L-LK7 and D-LK7 could inhibit Aβ aggregation in a concentration-dependent manner, it was the d-enantiomer that exhibited chirality preference and selectivity for modulation of Aβ self-assembly. As compared with L-LK7 at the same conditions, D-LK7 showed significantly enhanced potency on suppressing cross-β sheet formation, fibrillar Aβ aggregates deposition, Aβ conformational transition, and Aβ-triggered neurotoxicity on cultured cells. For instance, L-LK7 and D-LK7 rescued cells by increasing cell viability from 60% to 62% and 84% at 100?μmol·L^?1, respectively. The chiral discrimination of L-LK7 and D-LK7 was further validated by the different elimination efficiency on amyloid accumulation in AD model nematodes. It is considered that the higher binding affinity of D-LK7 to Aβ monomers than that of L-LK7 resulted in the stronger inhibition effect. This work provided new insights into understanding chirality in the interaction with Aβ and the consequent inhibitory effect, and would contribute to the design of anti-amyloid agents.

关键词: Alzheimer’s disease, Amyloid-β protein, Protein aggregation, Chirality, Inhibitor, Heptapeptide

Abstract: The modulation of protein aggregation is involved not only in biochemical engineering processes, but also in in vivo biological events such as Alzheimer’s disease (AD) that features amyloid-β protein (Aβ) deposits. Inspired by the different pharmacological efficacy of enantiomers, taking heptapeptide LVFFARK (LK7) as an example, herein the chiral influence of peptide inhibitors on Aβ fibrillogenesis and cytotoxicity was investigated by extensive biophysical and biological analyses. It was intriguing to find that although both L-LK7 and D-LK7 could inhibit Aβ aggregation in a concentration-dependent manner, it was the d-enantiomer that exhibited chirality preference and selectivity for modulation of Aβ self-assembly. As compared with L-LK7 at the same conditions, D-LK7 showed significantly enhanced potency on suppressing cross-β sheet formation, fibrillar Aβ aggregates deposition, Aβ conformational transition, and Aβ-triggered neurotoxicity on cultured cells. For instance, L-LK7 and D-LK7 rescued cells by increasing cell viability from 60% to 62% and 84% at 100?μmol·L^?1, respectively. The chiral discrimination of L-LK7 and D-LK7 was further validated by the different elimination efficiency on amyloid accumulation in AD model nematodes. It is considered that the higher binding affinity of D-LK7 to Aβ monomers than that of L-LK7 resulted in the stronger inhibition effect. This work provided new insights into understanding chirality in the interaction with Aβ and the consequent inhibitory effect, and would contribute to the design of anti-amyloid agents.

Key words: Alzheimer’s disease, Amyloid-β protein, Protein aggregation, Chirality, Inhibitor, Heptapeptide

Wei Liu, Xueting Sun, Xiaoyan Dong, Yan Sun. Chiral LVFFARK enantioselectively inhibits amyloid-β protein fibrillogenesis[J]. 中国化学工程学报, 2022, 48(8): 227-235.

Wei Liu, Xueting Sun, Xiaoyan Dong, Yan Sun. Chiral LVFFARK enantioselectively inhibits amyloid-β protein fibrillogenesis[J]. Chinese Journal of Chemical Engineering, 2022, 48(8): 227-235.

参考文献

[1] F.U. Hartl, Protein misfolding diseases, Annu Rev Biochem 86 (2017) 21–26
[2] N. Levy, S. Eiler, K. Pradeau-Aubreton, B. Maillot, F. Stricher, M. Ruff, Production of unstable proteins through the formation of stable core complexes, Nat Commun 7 (2016) 10932
[3] Y.X. Zhang, Y.J. Tang, D. Zhang, Y.L. Liu, J. He, Y. Chang, J. Zheng, Amyloid cross-seeding between Aβ and hIAPP in relation to the pathogenesis of Alzheimer and type 2 diabetes, Chin. J. Chem. Eng. 30 (2021) 225–235
[4] T.P. Knowles, M. Vendruscolo, C.M. Dobson, The amyloid state and its association with protein misfolding diseases, Nat Rev Mol Cell Biol 15 (6) (2014) 384–396
[5] C. Haass, D.J. Selkoe, Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer's amyloid beta-peptide, Nat Rev Mol Cell Biol 8 (2) (2007) 101–112
[6] C. Patterson, World Alzheimer Report 2018-The State of The Art of Dementia Research: New frontiers. (Alzheime's Disease International (ADI), London, UK, 2018)
[7] Mohamed T, Shakeri A, Rao PP, Amyloid cascade in Alzheimer's disease: Recent advances in medicinal chemistry, Eur J Med Chem 113 (2016) 258–272
[8] J. Hardy, D.J. Selkoe, The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics, Science 297 (5580) (2002) 353–356
[9] Huang Y, Mucke L, Alzheimer mechanisms and therapeutic strategies, Cell 148 (6) (2012) 1204–1222
[10] D. Goyal, S. Shuaib, S. Mann, B. Goyal, Rationally designed peptides and peptidomimetics as inhibitors of amyloid-β (aβ) aggregation: Potential therapeutics of Alzheimer's disease, ACS Comb Sci 19 (2) (2017) 55–80
[11] W. Liu, X.Y. Dong, Y. Liu, Y. Sun, Photoresponsive materials for intensified modulation of Alzheimer's amyloid-β protein aggregation: A review, Acta Biomater 123 (2021) 93–109
[12] P.C. Ke, E.H. Pilkington, Y.X. Sun, I. Javed, A. Kakinen, G.T. Peng, F. Ding, T.P. Davis, Amyloidosis: Mitigation of amyloidosis with nanomaterials (adv. mater. 18/2020), Adv. Mater. 32 (18) (2020) 2070146
[13] M. Zhang, X.B. Mao, Y. Yu, C.X. Wang, Y.L. Yang, C. Wang, Nanomaterials for reducing amyloid cytotoxicity, Adv Mater 25 (28) (2013) 3780–3801
[14] J. Sevigny, P. Chiao, T. Bussière, P.H. Weinreb, L. Williams, M. Maier, R. Dunstan, S. Salloway, T.L. Chen, Y. Ling, J. O'Gorman, F. Qian, M. Arastu, M.W. Li, S. Chollate, M.S. Brennan, O. Quintero-Monzon, R.H. Scannevin, H.M. Arnold, T. Engber, K. Rhodes, J. Ferrero, Y.M. Hang, A. Mikulskis, J. Grimm, C. Hock, R.M. Nitsch, A. Sandrock, The antibody aducanumab reduces Aβ plaques in Alzheimer's disease, Nature 537 (7618) (2016) 50–56
[15] F.F. Liu, W.P. Zhao, F. Zhao, Q.C. Dong, Y. Wang, W. Wei, L.G. Jia, L. Li, F.P. Lu, Dual effect of the acidic polysaccharose ulvan on the inhibition of amyloid-β protein fibrillation and disintegration of mature fibrils, ACS Appl Mater Interfaces 12 (37) (2020) 41167–41176
[16] D.J. Craik, D.P. Fairlie, S. Liras, D. Price, The future of peptide-based drugs, Chem Biol Drug Des 81 (1) (2013) 136–147
[17] S. Bansal, I.K. Maurya, N. Yadav, C.K. Thota, V. Kumar, K. Tikoo, V.S. Chauhan, R. Jain, C-terminal fragment, Aβ32-37, analogues protect against aβ aggregation-induced toxicity, ACS Chem Neurosci 7 (5) (2016) 615–623
[18] P.N. Cheng, C. Liu, M.L. Zhao, D. Eisenberg, J.S. Nowick, Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity, Nat Chem 4 (11) (2012) 927–933
[19] A.N. Klein, T. Ziehm, T. van Groen, I. Kadish, A. Elfgen, M. Tusche, M. Thomaier, K. Reiss, O. Brener, L. Gremer, J. Kutzsche, D. Willbold, Optimization of d-peptides for aβ monomer binding specificity enhances their potential to eliminate toxic aβ oligomers, ACS Chem Neurosci 8 (9) (2017) 1889–1900
[20] J. Liu, W. Wang, Q. Zhang, S.H. Zhang, Z. Yuan, Study on the efficiency and interaction mechanism of a decapeptide inhibitor of β-amyloid aggregation, Biomacromolecules 15 (3) (2014) 931–939
[21] N. Xiong, X.Y. Dong, J. Zheng, F.F. Liu, Y. Sun, Design of LVFFARK and LVFFARK-functionalized nanoparticles for inhibiting amyloid β-protein fibrillation and cytotoxicity, ACS Appl Mater Interfaces 7 (10) (2015) 5650–5662
[22] H. Zhang, X.Y. Dong, F.F. Liu, J. Zheng, Y. Sun, Ac-LVFFARK-NH2 conjugation to β-cyclodextrin exhibits significantly enhanced performance on inhibiting amyloid β-protein fibrillogenesis and cytotoxicity, Biophys Chem 235 (2018) 40–47
[23] H. Zhang, C. Zhang, X.Y. Dong, J. Zheng, Y. Sun, Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu2+ -mediated amyloid β-protein aggregation and cytotoxicity, J Mol Recognit 31 (6) (2018) e2697
[24] N. Gao, Z. Du, Y.J. Guan, K. Dong, J.S. Ren, X.G. Qu, Chirality-selected chemical modulation of amyloid aggregation, J. Am. Chem. Soc. 141 (17) (2019) 6915–6921
[25] D.D. Sun, W.W. Zhang, Q.Q. Yu, X. Chen, M. Xu, Y.H. Zhou, J. Liu, Chiral penicillamine-modified selenium nanoparticles enantioselectively inhibit metal-induced amyloid β aggregation for treating Alzheimer's disease, J Colloid Interface Sci 505 (2017) 1001–1010
[26] W.F. Kean, H.E. Howard-Lock, C.J.L. Lock, Chirality in antirheumatic drugs, Lancet 338 (8782–8783) (1991) 1565–1568
[27] G. Nystr?m, M. Arcari, R. Mezzenga, Confinement-induced liquid crystalline transitions in amyloid fibril cholesteric tactoids, Nat. Nanotechnol. 13 (4) (2018) 330–336
[28] G.Y. Qing, S.L. Zhao, Y. Xiong, Z. Lv, F.L. Jiang, Y. Liu, H. Chen, M.X. Zhang, T.L. Sun, Chiral effect at protein/graphene interface: A bioinspired perspective to understand amyloid formation, J Am Chem Soc 136 (30) (2014) 10736–10742
[29] N. Rubin, E. Perugia, M. Goldschmidt, M. Fridkin, L. Addadi, Chirality of amyloid suprastructures, J. Am. Chem. Soc. 130 (14) (2008) 4602–4603
[30] X.B. Zhou, J. Sun, T.T. Yin, F.L. Le, L.C. Yang, Y.N. Liu, J. Liu, Enantiomers of cysteine-modified SeNPs (d/lSeNPs) as inhibitors of metal-induced Aβ aggregation in Alzheimer's disease, J. Mater. Chem. B 3 (39) (2015) 7764–7774
[31] K. Wiesehan, J. St?hr, L. Nagel-Steger, T. van Groen, D. Riesner, D. Willbold, Inhibition of cytotoxicity and amyloid fibril formation by a D-amino acid peptide that specifically binds to Alzheimer's disease amyloid peptide, Protein Eng Des Sel 21 (4) (2008) 241–246
[32] W. Liu, W.J. Wang, X.Y. Dong, Y. Sun, Near-infrared light-powered Janus nanomotor significantly facilitates inhibition of amyloid-β fibrillogenesis, ACS Appl Mater Interfaces 12 (11) (2020) 12618–12628
[33] O. Trott, A.J. Olson, AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, J Comput Chem 31 (2) (2010) 455–461
[34] S. Vivekanandan, J.R. Brender, S.Y. Lee, A. Ramamoorthy, A partially folded structure of amyloid-beta(1-40) in an aqueous environment, Biochem Biophys Res Commun 411 (2) (2011) 312–316
[35] O. Crescenzi, S. Tomaselli, R. Guerrini, S. Salvadori, A.M. D'Ursi, P.A. Temussi, D. Picone, Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar microenvironment. Similarity with a virus fusion domain, Eur J Biochem 269 (22) (2002) 5642–5648
[36] W. Liu, X.Y. Dong, Y. Sun, D-enantiomeric RTHLVFFARK-NH2: A potent multifunctional decapeptide inhibiting Cu2+-mediated amyloid β-protein aggregation and remodeling Cu2+-mediated amyloid β aggregates, ACS Chem. Neurosci. 10 (3) (2019) 1390–1401
[37] K. Hou, J. Zhao, H. Wang, B. Li, K.X. Li, X.H. Shi, K.W. Wan, J. Ai, J. Lv, D.W. Wang, Q.X. Huang, H.Y. Wang, Q. Cao, S.Q. Liu, Z.Y. Tang, Chiral gold nanoparticles enantioselectively rescue memory deficits in a mouse model of Alzheimer's disease, Nat Commun 11 (1) (2020) 4790
[38] M. Li, S.E. Howson, K. Dong, N. Gao, J.S. Ren, P. Scott, X.G. Qu, Chiral metallohelical complexes enantioselectively target amyloid β for treating Alzheimer's disease, J Am Chem Soc 136 (33) (2014) 11655–11663
[39] S. Ma, H. Zhang, X.Y. Dong, L.L. Yu, J. Zheng, Y. Sun, Head-to-tail cyclization of a heptapeptide eliminates its cytotoxicity and significantly increases its inhibition effect on amyloid β-protein fibrillation and cytotoxicity, Front. Chem. Sci. Eng. 12 (2) (2018) 283–295
[40] W.Q. Gao, W.J. Wang, X.Y. Dong, Y. Sun, Nitrogen-doped carbonized polymer dots: A potent scavenger and detector targeting Alzheimer's β-amyloid plaques, Small 16 (43) (2020) 2002804
[41] Y. Liang, W.J. Wang, Y. Sun, X.Y. Dong, Insights into the cross-amyloid aggregation of Aβ40 and its N-terminal truncated peptide Aβ11-40 affected by epigallocatechin gallate, Chin. J. Chem. Eng. (2022) 284-293.

Chiral LVFFARK enantioselectively inhibits amyloid-β protein fibrillogenesis

Chiral LVFFARK enantioselectively inhibits amyloid-β protein fibrillogenesis

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	Huan-Huan Yin, Yin-Lei Han, Xiao Yan, Yi-Xin Guan. Proanthocyanidins prevent tau protein aggregation and disintegrate tau filaments[J]. 中国化学工程学报, 2023, 57(5): 63-71.
[2]	Suhang Xun, Cancan Wu, Lida Tang, Mengmeng Yuan, Haofeng Chen, Minqiang He, Wenshuai Zhu, Huaming Li. One-pot in-situ synthesis of coralloid supported VO₂ catalyst for intensified aerobic oxidative desulfurization[J]. 中国化学工程学报, 2023, 56(4): 136-140.
[3]	Xing Huang, Ran Zhu, Liwei Cheng, Yijian Zhu, Peng Xiao, Xiaohui Wang, Bei Liu, Changyu Sun, Weixin Pang, Qingping Li, Guangjin Chen, Xinjing Xu, Jinfeng Ji. Synthesis and evaluation of poly (N-vinyl caprolactam)-co-tert-butyl acrylate as kinetic hydrate inhibitor[J]. 中国化学工程学报, 2022, 50(10): 317-325.
[4]	Yanping Duan, Pengfei Wang, Wenge Yang, Xia Zhao, Hong Hao, Ruijie Wu, Jie Huang. Experimental and density functional theory computational evaluation of poly(N-vinyl caprolactam-co-butyl methacrylate) kinetic hydrate inhibitors[J]. 中国化学工程学报, 2021, 40(12): 237-244.
[5]	Abdelaziz S. Fouda, Mohamed A. Ismail, Rabab M. Abou-shahba, Walaa A. Husien, Esraa S. EL-Habab, Ashraf S. Abousalem. Experimental and computational chemical studies on the cationic furanylnicotinamidines as novel corrosion inhibitors in aqueous solutions[J]. 中国化学工程学报, 2020, 28(2): 477-491.
[6]	M. Lavanya, V. Ramachandra Murthy, Padmalatha Rao. Erosion corrosion control of 6061 aluminum alloy in multi-phase jet impingement conditions with eco-friendly green inhibitor[J]. 中国化学工程学报, 2020, 28(2): 340-347.
[7]	Sheshan Bhimrao Meshram, Omkar S Kushwaha, Palle Ravinder Reddy, Gaurav Bhattacharjee, Rajnish Kumar. Investigation on the effect of oxalic acid, succinic acid and aspartic acid on the gas hydrate formation kinetics[J]. 中国化学工程学报, 2019, 27(9): 2148-2156.
[8]	Yanhong Wang, Shuanshi Fan, Xuemei Lang. Reviews of gas hydrate inhibitors in gas-dominant pipelines and application of kinetic hydrate inhibitors in China[J]. 中国化学工程学报, 2019, 27(9): 2118-2132.
[9]	Cuiping Tang, Deqing Liang. Inhibitory effects of novel green inhibitors on gas hydrate formation[J]. 中国化学工程学报, 2019, 27(9): 2107-2117.
[10]	Wei Ke, Daoyi Chen. A short review on natural gas hydrate, kinetic hydrate inhibitors and inhibitor synergists[J]. 中国化学工程学报, 2019, 27(9): 2049-2061.
[11]	Xianghong Li, Shuduan Deng, Xiaoguang Xie. Red tetrazolium as an effective inhibitor for the corrosion of cold rolled steel in 7.0 mol·L^-1 H₂SO₄ solution[J]. Chinese Journal of Chemical Engineering, 2018, 26(12): 2641-2653.
[12]	Charitha B. P., Padmalatha Rao. An ecofriendly approach for corrosion control of 6061 Al-15%_(v) SiC_(P) composite and its base alloy[J]. , 2017, 25(3): 363-372.
[13]	R. Geethanjali, S. Subhashini. Synthesis of water-soluble acryl terpolymers and their anticorrosion properties on mild steel in 1 mol·L^-1 HCl[J]. Chinese Journal of Chemical Engineering, 2016, 24(4): 543-552.
[14]	Ekemini Ituen, Abosede James, Onyewuchi Akaranta, Shuangqin Sun. Eco-friendly corrosion inhibitor from Pennisetum purpureum biomass and synergistic intensifiers for mild steel[J]. , 2016, 24(10): 1442-1447.
[15]	Yan Fu, Jinjin Yang, Jinli Zhang, Wei Li. Bio-inspired enantioseparation for chiral compounds[J]. Chinese Journal of Chemical Engineering, 2016, 24(1): 31-38.