{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T03:00:07Z","timestamp":1760151607248,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T00:00:00Z","timestamp":1649116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["21-74-00069"],"award-info":[{"award-number":["21-74-00069"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Polymers"],"abstract":"<jats:p>Amyloid aggregation, including aggregation and propagation of prion protein, is a key factor in numerous human diseases, so-called amyloidosis, with a very poor ability for treatment or prevention. The present work describes the effect of sulfated or sulfonated polymers (sodium dextran sulfate, polystyrene sulfonate, polyanethole sulfonate, and polyvinyl sulfate) on different stages of amyloidogenic conversion and aggregation of the prion protein, which is associated with prionopathies in humans and animals. All tested polymers turned out to induce amyloid conversion of the ovine prion protein. As suggested from molecular dynamics simulations, this effect probably arises from destabilization of the native prion protein structure by the polymers. Short polymers enhanced its further aggregation, whereas addition of high-molecular poly(styrene sulfonate) inhibited amyloid fibrils formation. According to the seeding experiments, the protein\u2013polymer complexes formed after incubation with poly(styrene sulfonate) exhibited significantly lower amyloidogenic capacity compared with the control fibrils of the free prion protein. The cytotoxicity of soluble oligomers was completely inhibited by treatment with poly(styrene sulfonate). To summarize, sulfonated polymers are a promising platform for the formulation of a new class of anti-prion and anti-amyloidosis therapeutics.<\/jats:p>","DOI":"10.3390\/polym14071478","type":"journal-article","created":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T11:26:07Z","timestamp":1649157967000},"page":"1478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Synthetic Sulfated Polymers Control Amyloid Aggregation of Ovine Prion Protein and Decrease Its Toxicity"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7759-6445","authenticated-orcid":false,"given":"Pavel","family":"Semenyuk","sequence":"first","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Evstafyeva","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir","family":"Izumrudov","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir","family":"Muronetz","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1080\/13506129.2016.1257986","article-title":"Amyloid Fibril Proteins and Amyloidosis: Chemical Identification and Clinical Classification International Society of Amyloidosis 2016 Nomenclature Guidelines","volume":"23","author":"Sipe","year":"2016","journal-title":"Amyloid"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/s41580-018-0060-8","article-title":"A New Era for Understanding Amyloid Structures and Disease","volume":"19","author":"Iadanza","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1152\/physrev.00006.2009","article-title":"Prions: Protein Aggregation and Infectious Diseases","volume":"89","author":"Aguzzi","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1146\/annurev.pathmechdis.3.121806.154326","article-title":"Molecular Mechanisms of Prion Pathogenesis","volume":"3","author":"Aguzzi","year":"2008","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1056\/NEJM200105173442006","article-title":"Neurodegenerative Diseases and Prions","volume":"344","author":"Prusiner","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3389\/fnins.2017.00277","article-title":"Possible Function of Molecular Chaperones in Diseases Caused by Propagating Amyloid Aggregates","volume":"11","author":"Lazarev","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s11010-013-1844-y","article-title":"Association of Heat-Shock Proteins in Various Neurodegenerative Disorders: Is It a Master Key to Open the Therapeutic Door?","volume":"386","author":"Paul","year":"2014","journal-title":"Mol. Cell. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1126\/science.7754373","article-title":"Role of the Chaperone Protein Hsp104 in Propagation of the Yeast Prion-like Factor [Psi+]","volume":"268","author":"Chernoff","year":"1995","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1073\/pnas.97.4.1589","article-title":"Aggregation of Huntingtin in Yeast Varies with the Length of the Polyglutamine Expansion and the Expression of Chaperone Proteins","volume":"97","author":"Krobitsch","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1128\/MCB.19.2.1325","article-title":"Antagonistic Interactions between Yeast Chaperones Hsp104 and Hsp70 in Prion Curing","volume":"19","author":"Newnam","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"425","DOI":"10.3233\/JAD-130779","article-title":"Therapeutic Effect of Exogenous Hsp70 in Mouse Models of Alzheimer\u2019s Disease","volume":"38","author":"Bobkova","year":"2014","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.ijbiomac.2018.10.031","article-title":"Artificial Chaperones Based on Thermoresponsive Polymers Recognize the Unfolded State of the Protein","volume":"121","author":"Semenyuk","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1021\/bm049501t","article-title":"Thermoresponsive Controlled Association of Protein with a Dynamic Nanogel of Hydrophobized Polysaccharide and Cyclodextrin:\u2009 Heat Shock Protein-Like Activity of Artificial Molecular Chaperone","volume":"6","author":"Nomura","year":"2005","journal-title":"Biomacromolecules"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1021\/bm5005756","article-title":"Prevention of Thermally Induced Aggregation of IgG Antibodies by Noncovalent Interaction with Poly(Acrylate) Derivatives","volume":"15","author":"Martin","year":"2014","journal-title":"Biomacromolecules"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1021\/la503643q","article-title":"Prevention of Aggregation and Renaturation of Carbonic Anhydrase via Weak Association with Octadecyl- or Azobenzene-Modified Poly(Acrylate) Derivatives","volume":"31","author":"Martin","year":"2015","journal-title":"Langmuir"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1002\/mabi.200500142","article-title":"Interaction of Polyanions with Basic Proteins, 2(a): Influence of Complexing Polyanions on the Thermo-Aggregation of Oligomeric Enzymes","volume":"5","author":"Shalova","year":"2005","journal-title":"Macromolar Biosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.abb.2014.12.021","article-title":"Sulfated and Sulfonated Polymers Are Able to Solubilize Efficiently the Protein Aggregates of Different Nature","volume":"567","author":"Semenyuk","year":"2015","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1021\/bm060229s","article-title":"Molecular Interactions of Dendrimers with Amyloid Peptides:\u2009 PH Dependence","volume":"7","author":"Klajnert","year":"2006","journal-title":"Biomacromolecules"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.bbrc.2006.04.041","article-title":"Influence of Dendrimer\u2019s Structure on Its Activity against Amyloid Fibril Formation","volume":"345","author":"Klajnert","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/S1474-4422(03)00484-8","article-title":"Heparan Sulphate Proteoglycans in Alzheimer\u2019s Disease and Amyloid-related Disorders","volume":"2","author":"Wesseling","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2510","DOI":"10.3390\/molecules20022510","article-title":"The Effect of Glycosaminoglycans (GAGs) on Amyloid Aggregation and Toxicity","volume":"20","author":"Iannuzzi","year":"2015","journal-title":"Molecules"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s10719-017-9769-4","article-title":"Sulfated Glycosaminoglycans in Protein Aggregation Diseases","volume":"34","author":"Nishitsuji","year":"2017","journal-title":"Glycoconj. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1046\/j.1432-1327.1999.00957.x","article-title":"Interactions of Alzheimer Amyloid-\u03b2 Peptides with Glycosaminoglycans","volume":"266","author":"McLaurin","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.neures.2009.12.012","article-title":"Aggregation and Cytotoxic Properties towards Cultured Cerebrovascular Cells of Dutch-Mutated A\u03b240 (DA\u03b21-40) Are Modulated by Sulfate Moieties of Heparin","volume":"66","author":"Timmer","year":"2010","journal-title":"Neurosci. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1021\/bi011711s","article-title":"Heparin and Other Glycosaminoglycans Stimulate the Formation of Amyloid Fibrils from \u03b1-Synuclein in Vitro","volume":"41","author":"Cohlberg","year":"2002","journal-title":"Biochemistry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"33118","DOI":"10.1074\/jbc.272.52.33118","article-title":"Alzheimer-like Changes in Microtubule-Associated Protein Tau Induced by Sulfated Glycosaminoglycans. Inhibition of Microtubule Binding, Stimulation of Phosphorylation, and Filament Assembly Depend on the Degree of Sulfation","volume":"272","author":"Hasegawa","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1007\/s10930-017-9728-8","article-title":"Learning from Synthetic Models of Extracellular Matrix; Differential Binding of Wild Type and Amyloidogenic Human Apolipoprotein A-I to Hydrogels Formed from Molecules Having Charges Similar to Those Found in Natural GAGs","volume":"36","author":"Toledo","year":"2017","journal-title":"Protein J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1021\/acs.biochem.6b01120","article-title":"Heparin and Methionine Oxidation Promote the Formation of Apolipoprotein A-I Amyloid Comprising \u03b1-Helical and \u03b2-Sheet Structures","volume":"56","author":"Townsend","year":"2017","journal-title":"Biochemistry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.1021\/bi101905n","article-title":"Heparin Binds 8 KDa Gelsolin Cross-\u03b2-Sheet Oligomers and Accelerates Amyloidogenesis by Hastening Fibril Extension","volume":"50","author":"Solomon","year":"2011","journal-title":"Biochemistry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.abb.2017.12.016","article-title":"Acceleration of Amyloid Fibril Formation by Carboxyl-Terminal Truncation of Human Serum Amyloid A","volume":"639","author":"Tanaka","year":"2018","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Semenyuk, P., Kurochkina, L., Barinova, K., and Muronetz, V. (2020). Alpha-Synuclein Amyloid Aggregation Is Inhibited by Sulfated Aromatic Polymers and Pyridinium Polycation. Polymers, 12.","DOI":"10.3390\/polym12030517"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1128\/jvi.67.2.643-650.1993","article-title":"Sulfated Polyanion Inhibition of Scrapie-Associated PrP Accumulation in Cultured Cells","volume":"67","author":"Caughey","year":"1993","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3768","DOI":"10.1039\/C8SM00101D","article-title":"Tightly Bound Polyelectrolytes Enhance Enzyme Proteolysis and Destroy Amyloid Aggregates","volume":"14","author":"Evstafyeva","year":"2018","journal-title":"Soft Matter"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Semenyuk, P., and Muronetz, V. (2019). Protein Interaction with Charged Macromolecules: From Model Polymers to Unfolded Proteins and Post-Translational Modifications. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051252"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3882","DOI":"10.1002\/anie.202006457","article-title":"Understanding the Interaction of Polyelectrolyte Architectures with Proteins and Biosystems","volume":"60","author":"Achazi","year":"2021","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1021\/ct301118j","article-title":"Decrypting Prion Protein Conversion into a \u03b2-Rich Conformer by Molecular Dynamics","volume":"9","author":"Chakroun","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1021\/acschemneuro.6b00109","article-title":"Impact of Cu(II) Binding on Structures and Dynamics of A\u03b242 Monomer and Dimer: Molecular Dynamics Study","volume":"7","author":"Huy","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1080\/07391102.2015.1113890","article-title":"Zinc-Induced Heterodimer Formation between Metal-Binding Domains of Intact and Naturally Modified Amyloid-Beta Species: Implication to Amyloid Seeding in Alzheimer\u2019s Disease?","volume":"34","author":"Mezentsev","year":"2016","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3518","DOI":"10.1021\/cr500638n","article-title":"Amyloid \u03b2 Protein and Alzheimer\u2019s Disease: When Computer Simulations Complement Experimental Studies","volume":"115","author":"Nguyen","year":"2015","journal-title":"Chem. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"138","DOI":"10.4103\/0972-2327.144284","article-title":"Toxic Species in Amyloid Disorders: Oligomers or Mature Fibrils","volume":"18","author":"Verma","year":"2015","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1007\/s00401-017-1755-1","article-title":"Alpha-Synuclein Oligomers: A New Hope","volume":"134","author":"Roberts","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1001\/archneurol.2007.56","article-title":"Protein Misfolding and Neurodegeneration","volume":"65","author":"Soto","year":"2008","journal-title":"Arch. Neurol."},{"key":"ref_43","first-page":"2833","article-title":"High Yield Purification and Physico-Chemical Properties of Full-Length Recombinant Allelic Variants of Sheep Prion Protein Linked to Scrapie Susceptibility","volume":"267","author":"Rezaei","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.jmb.2005.01.043","article-title":"Sequential Generation of Two Structurally Distinct Ovine Prion Protein Soluble Oligomers Displaying Different Biochemical Reactivities","volume":"347","author":"Rezaei","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wilham, J.M., Orr\u00fa, C.D., Bessen, R.A., Atarashi, R., Sano, K., Race, B., Meade-White, K.D., Taubner, L.M., Timmes, A., and Caughey, B. (2010). Rapid End-Point Quantitation of Prion Seeding Activity with Sensitivity Comparable to Bioassays. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1001217"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7821","DOI":"10.1039\/c0cp00111b","article-title":"The R.E.D. Tools: Advances in RESP and ESP Charge Derivation and Force Field Library Building","volume":"12","author":"Dupradeau","year":"2010","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_47","unstructured":"Granovsky, A.A. (2016, May 26). Firefly Version 8.0. Available online: http:\/\/classic.chem.msu.su\/gran\/gamess\/index.html."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1002\/jcc.540141112","article-title":"General Atomic and Molecular Electronic Structure System","volume":"14","author":"Schmidt","year":"1993","journal-title":"J. Comput. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High Performance Molecular Simulations through Multi-Level Parallelism from Laptops to Supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular Dynamics with Coupling to an External Bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1134\/S0006297910040061","article-title":"Structural Changes of a Protein Bound to a Polyelectrolyte Depend on the Hydrophobicity and Polymerization Degree of the Polyelectrolyte","volume":"75","author":"Stogov","year":"2010","journal-title":"Biochem. Mosc."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1002\/pro.281","article-title":"The Hofmeister Effect on Amyloid Formation Using Yeast Prion Protein","volume":"19","author":"Yeh","year":"2010","journal-title":"Protein Sci. Publ. Protein Soc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1046\/j.1471-4159.1999.721681.x","article-title":"The Sulfate Moieties of Glycosaminoglycans Are Critical for the Enhancement of \u03b2-Amyloid Protein Fibril Formation","volume":"72","author":"Castillo","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1080\/13506120601116419","article-title":"Heparan Sulfate as a Therapeutic Target in Amyloidogenesis: Prospects and Possible Complications","volume":"14","author":"Kisilevsky","year":"2007","journal-title":"Amyloid"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1007\/PL00021763","article-title":"Biochemical Effects of Molecular Crowding","volume":"69","author":"Chebotareva","year":"2004","journal-title":"Biochem. Mosc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"9829","DOI":"10.1021\/acs.jpcb.0c07175","article-title":"Investigating the Effects of Molecular Crowding on the Kinetics of Protein Aggregation","volume":"124","author":"Schreck","year":"2020","journal-title":"J. Phys. Chem. B"},{"key":"ref_57","first-page":"36","article-title":"Practice of \u201cLomonosov\u201d supercomputer","volume":"7","author":"Voevodin","year":"2012","journal-title":"Open Syst. J."}],"container-title":["Polymers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4360\/14\/7\/1478\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:48:47Z","timestamp":1760136527000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4360\/14\/7\/1478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,5]]},"references-count":57,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["polym14071478"],"URL":"https:\/\/doi.org\/10.3390\/polym14071478","relation":{},"ISSN":["2073-4360"],"issn-type":[{"type":"electronic","value":"2073-4360"}],"subject":[],"published":{"date-parts":[[2022,4,5]]}}}