Nanochaperones Based on Hydrophobic Interaction and Coordination Inhibit Protein Misfolding and Fibrillation

Hui Wang; Lin-Lin Xu; Lin-Qi Shi; Ru-Jiang Ma

doi:10.1007/s10118-024-3169-6

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Nanochaperones Based on Hydrophobic Interaction and Coordination Inhibit Protein Misfolding and Fibrillation

RESEARCH ARTICLE | Updated：2024-11-04

- Nanochaperones Based on Hydrophobic Interaction and Coordination Inhibit Protein Misfolding and Fibrillation
- Chinese Journal of Polymer Science Vol. 42, Issue 11, Pages: 1710-1718(2024)
- Affiliations：
  
  a.Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China
  b.Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, China
- Author bio：
  
  shilinqi@nankai.edu.cn (L.Q.S.)
  marujiang@nankai.edu.cn (R.J.M.)
- Funds：
- DOI：10.1007/s10118-024-3169-6
  CLC：
- Published：30 November 2024，
  
  Published Online：20 August 2024，
  
  Received：23 April 2024，
  
  Revised：18 May 2024，
  
  Accepted：21 May 2024
- Accepted：
Scan QR Code
Wang, H.; Xu, L. L.; Shi, L. Q.; Ma, R. J. Nanochaperones based on hydrophobic interaction and coordination inhibit protein misfolding and fibrillation. Chinese J. Polym. Sci. 2024, 42, 1710–1718

Hui Wang, Lin-Lin Xu, Lin-Qi Shi, et al. Nanochaperones Based on Hydrophobic Interaction and Coordination Inhibit Protein Misfolding and Fibrillation. [J]. Chinese Journal of Polymer Science, 2024,42(11):1710-1718.
Wang, H.; Xu, L. L.; Shi, L. Q.; Ma, R. J. Nanochaperones based on hydrophobic interaction and coordination inhibit protein misfolding and fibrillation. Chinese J. Polym. Sci. 2024, 42, 1710–1718 DOI： 10.1007/s10118-024-3169-6.

Hui Wang, Lin-Lin Xu, Lin-Qi Shi, et al. Nanochaperones Based on Hydrophobic Interaction and Coordination Inhibit Protein Misfolding and Fibrillation. [J]. Chinese Journal of Polymer Science, 2024,42(11):1710-1718. DOI： 10.1007/s10118-024-3169-6.

摘要

The researchers developed a nanochaperone called nChap-NA

which effectively trap the amyloid monomer and block its fibrillation site by the hydrophobic interaction of the PNIPAM microdomain and the coordination of NTA(Zn). This study may provide a promising strategy for the prophylactic treatment of amyloidosis.

Abstract

Amyloidosis is characterized by the deposition of fibrillar aggregates

with a specific peptide or protein as the primary component

in affected tissues or organs. Excessive proliferation and deposition of amyloid fibrils can cause organismal dysfun

ction and lethal pathological outcomes associated with amyloidosis. In this study

a nanochaperone (nChap-NA) was developed to inhibit protein misfolding and fibrillation by simulating the function of natural molecular chaperones. The nanochaperone was prepared by self-assembly of two block copolymers PEG-

-PCL and PCL-

-P(NIPAM-

-AANTA)

which had a phase-separated surface consisting of hydrophobic PNIPAM microdomains with coordinative NTA(Zn) moieties and hydrophilic PEG chains. The hydrophobic interaction of the PNIPAM microdomain and the coordination of NTA(Zn) synergistically work together to effectively trap the amyloid monomer and block its fibrillation site. Insulin and human islet amyloid polypeptide (hIAPP) were used as model proteins to investigate the nanochaperone's inhibition of amyloid misfolding and fibrillation. It was proved that the nanochaperone could stabilize the natural conformation of the trapped insulin and hIAPP

and effectively inhibit their fibrillation.

In vivo

study demonstrated that the nanochaperone could effectively preserve the bioactivity of insulin and reduce the cytotoxicity caused by hIAPP aggregation. This study may provide a promising strategy for the prophylactic treatment of amyloidosis.

关键词

Keywords

NanochaperoneAmyloidosisInsulinhIAPPInhibit fibrillation

references

Ghosh, P.; De, P. Modulation of amyloid protein fibrillation by synthetic polymers: recent advances in the context of neurodegenerative diseases.ACS Appl. Bio Mater.2020,3, 6598−6625..

Brange, J.; Dodson, G.; Edwards, D.; Holden, P.; Whittingham, J. A model of insulin fibrils derived from the X-ray crystal structure of a monomeric insulin (despentapeptide insulin).Proteins1997,27, 507−516..

Ghosh, P.; Bera, A.; Bhadury, P.; De, P. From small molecules to synthesized polymers: potential role in combatingamyloidogenic disorders.ACS Chem. Neurosci.2021,12, 1737−1748..

Meisl, G.; Yang, X.; Frohm, B.; Knowles, T. P.; Linse, S. Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of alzheimer-associated aβ-peptide.Sci. Rep.2016,6, 18728..

Thacker, D.; Sanagavarapu, K.; Frohm, B.; Meisl, G.; Knowles, T. P.; Linse, S. The role of fibril structure and surface hydrophobicity in secondary nucleation of amyloid fibrils.Proc. Natl. Acad. Sci. U. S. A.2020,117, 25272−25283..

Chai, R.; Xing, C.; Qi, J.; Fan, Y.; Yuan, H.; Niu, R.; Zhan, Y.; Xu, J. Water-soluble conjugated polymers for the detection and inhibition of protein aggregation.Adv. Funct. Mater.2016,26, 9026−9031..

Alam, P.; Siddiqi, K.; Chturvedi, S. K.; Khan, R. H. Protein aggregation: from background to inhibition strategies.Int. J. Biol. Macromol.2017,103, 208−219..

Gao, N.; Liu, Z.; Zhang, H.; Liu, C.; Yu, D.; Ren, J.; Qu, X. Site-directed chemical modification of amyloid by polyoxometalates for inhibition of protein misfolding and aggregation.Angew. Chem. Int. Ed.2022,61, e202115336..

Sun, H.; Lv, F.; Liu, L.; Wang, S. Reactive conjugated polymers for the modulation of islet amyloid polypeptide assembly.ACS Appl. Mater. Interfaces2019,11, 22973−22978..

Poulson, B. G.; Szczepski, K.; Lachowicz, J. I.; Jaremko, L.; Emwas, A. H.; Jaremko, M. Aggregation of biologically important peptides and proteins: inhibition or acceleration depending on protein and metal ion concentrations.RSC Adv.2020,10, 215−227..

Sahoo, B. R.; Genjo, T.; Nakayama, T. W.; Stoddard, A. K.; Ando, T.; Yasuhara, K.; Fierke, C. A.; Ramamoorthy, A. A cationic polymethacrylate-copolymer acts as an agonist forβ-amyloid and an antagonist for amylin fibrillation.Chem. Sci.2019,10, 3976−3986..

Saravanan, M. S.; Ryazanov, S.; Leonov, A.; Nicolai, J.; Praest, P.; Giese, A.; Winter, R.; Khemtemourian, L.; Griesinger, C.; Killian, J. A. The small molecule inhibitor anle145c thermodynamically traps human islet amyloid peptide in the form of non-cytotoxic oligomers.Sci. Rep.2019,9, 19023..

Saraogi, I.; Hebda, J. A.; Becerril, J.; Estroff, L. A.; Miranker, A. D.; Hamilton, A. D. Synthetic α-helix mimetics as agonists and antagonists of iapp amyloid formation.Angew. Chem. Int. Ed.2010,49, 736..

Wang, H.; Abedini, A.; Ruzsicska, B.; Raleigh, D. P. Rationally designed, nontoxic, nonamyloidogenic analogues of human islet amyloid polypeptide with improved solubility.Biochemistry2014,53, 5876−5884..

Otvos, L. Jr.; Wade, J. D. Current challenges in peptide-based drug discovery.Front. Chem.2014,2, 62..

Sang, S.; Lee, M. J.; Hou, Z.; Ho, C. T.; Yang, C. S. Stability of tea polyphenol (−)-epigallocatechin-3-gallate and formation of dimers and epimers under common experimental conditions.J. Agric. Food Chem.2005,53, 9478−9484..

Palhano, F. L.; Lee, J.; Grimster, N. P.; Kelly, J. W. Toward the molecular mechanism (s) by which egcg treatment remodels mature amyloid fibrils.J. Am. Chem. Soc.2013,135, 7503−7510..

Martinez Pomier, K.; Ahmed, R.; Melacini, G. Catechins as tools to understand the molecular basis of neurodegeneration.Molecules2020,25, 3571..

Xu, Y.; Maya-Martinez, R.; Guthertz, N.; Heath, G. R.; Manfield, I. W.; Breeze, A. L.; Sobott, F.; Foster, R.; Radford, S. E. Tuning the rate of aggregation of hiapp into amyloid using small-molecule modulators of assembly.Nat. Commun.2022,13, 1040..

Hipp, M. S.; Park, S. H.; Hartl, F. U. Proteostasis impairment in protein-misfolding and-aggregation diseases.Trends Cell Biol.2014,24, 506−514..

Kampinga, H. H.; Bergink, S. Heat shock proteins as potential targets for protective strategies in neurodegeneration.Lancet Neurol.2016,15, 748−759..

Huang, F.; Wang, J.; Qu, A.; Shen, L.; Liu, J.; Liu, J.; Zhang, Z.; An, Y.; Shi, L. Maintenance of amyloidβpeptide homeostasis by artificial chaperones based on mixed-shell polymeric micelles.Angew. Chem. Int. Ed.2014,53, 8985−90..

Cui, L. Y.; Liu, S. A.; Wu, F.; Chen, H.; Li, Y. F.; Shi, L. Q.; Liu, Y.; Ma, R. J. Protein@pp-Zn nanocomplex assembled by coordination of zinc ions used for intracellular protein delivery.Sci. China Chem.2023,66, 2354−2362..

Hua, C.; Li, Y. C.; Yuan, F. L.; Yong, L.; Ru, J. M.; Lin, Q. S. Phenylboronic acid functionalized polymer nanocarriers for intracellular delivery of protein drugs.Acta Polymerica Sinica(in Chinese) 2023 ,54, 451-466..

Liu, S. N.; Meng, J. H.; Cui, L. Y.; Chen, H.; Shi, L. Q.; Ma, R. J. A dynamic covalent bonding-based nanoplatform for intracellular co-delivery of protein drugs and chemotherapeutics with enhanced anti-cancer effect.Chinese J. Polym. Sci.2024,42, 559−569..

Iadanza, M. G.; Jackson, M. P.; Hewitt, E. W.; Ranson, N. A.; Radford, S. E. A new era for understanding amyloid structures and disease.Nat. Rev. Mol. Cell Biol.2018,19, 755−773..

Lee, M.; Wang, T.; Makhlynets, O. V.; Wu, Y.; Polizzi, N. F.; Wu, H.; Gosavi, P. M.; Stöhr, J.; Korendovych, I. V.; DeGrado, W. F. Zinc-binding structure of a catalytic amyloid from solid-state nmr.Proc. Natl. Acad. Sci. U. S. A.2017,114, 6191−6196..

Wang, H.; Li, A.; Yang, M.; Zhao, Y.; Shi, L.; Ma, R. Self-assembled nanochaperones enable the disaggregation of amyloid insulin fibrils.Sci. China Chem.2022,65, 353−362..

Störkel, S.; Schneider, H.; Müntefering, H.; Kashiwagi, S. Iatrogenic, insulin-dependent, local amyloidosis.Lab. Invest.1983,48, 108−111..

Dische, F.; Wernstedt, C.; Westermark, G.; Westermark, P.; Pepys, M.; Rennie, J.; Gilbey, S.; Watkins, P. Insulin as an amyloid-fibril protein at sites of repeatedinsulin injections in a diabetic patient.Diabetologia1988,31, 158−161..

Biancalana, M.; Koide, S. Molecular mechanism of thioflavin-t binding to amyloid fibrils.Biochim. Biophys. Acta2010,1804, 1405−12..

Zhu, L.; Xu, L.; Wu, X.; Deng, F.; Ma, R.; Liu, Y.; Huang, F.; Shi, L. Tau-targeted multifunctional nanoinhibitor for Alzheimer’s disease.ACS Appl. Mater. Interfaces2021,13, 23328−23338..

Cabaleiro-Lago, C.; Quinlan-Pluck, F.; Lynch, I.; Lindman, S.; Minogue, A. M.; Thulin, E.; Walsh, D. M.; Dawson, K. A.; Linse, S. Inhibition of amyloidβprotein fibrillation by polymeric nanoparticles.J. Am. Chem. Soc.2008,130, 15437−15443..

Fezoui, Y.; Teplow, D. B. Kinetic studies of amyloidβ-protein fibril assembly: Differential effects ofα-helix stabilization.J. Biol. Chem.2002,277, 36948−36954..

Kotarek, J. A.; Johnson, K. C.; Moss, M. A. Quartz crystal microbalance analysis of growth kinetics for aggregation intermediates of the amyloid-βprotein.Anal. Biochem.2008,378, 15−24..

Press, M.; Jung, T.; König, J.; Grune, T.; Höhn, A. Protein aggregates and proteostasis in aging: amylin andβ-cell function.Mech. Ageing Dev.2019,177, 46−54..

Milardi, D.; Gazit, E.; Radford, S. E.; Xu, Y.; Gallardo, R. U.; Caflisch, A.; Westermark, G. T.; Westermark, P.; Rosa, C. L.; Ramamoorthy, A. Proteostasis of islet amyloid polypeptide: a molecular perspective of risk factors and protective strategies for type II diabetes.Chem. Rev.2021,121, 1845−1893..

Wineman-Fisher, V.; Atsmon-Raz, Y.; Miller, Y. Orientations of residues along theβ-arch of self-assembled amylin fibril-like structures lead to polymorphism.Biomacromolecules2015,16, 156−165..

Niu, H.; Hou, X.; Zhang, Y.; Wu, X.; Deng, F.; Huang, F.; Shi, L.; Ma, R. Self-assembled nanochaperones inhibit the aggregation of human islet amyloid polypeptide associated with type 2 diabetes.ACS Macro Lett.2021,10, 662−670..

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