Skip to main content
PMC home page
Prion logoLink to Prion
. 2007 Jan-Mar;1(1):32–35. doi: 10.4161/pri.1.1.4095

Self Assembly of Short Aromatic Peptides into Amyloid Fibrils and Related Nanostructures

Ehud Gazit ✉
PMCID: PMC2633705  PMID: 19164892

Abstract

The formation of amyloid fibrils is the hallmark of more than twenty human disorders of unrelated etiology. In all these cases, ordered fibrillar protein assemblies with a diameter of 7–10 nm are being observed. In spite of the great clinical important of amyloidassociated diseases, the molecular recognition and self-assembly processes that lead to the formation of the fibrils are not fully understood. One direction to decipher the mechanism of amyloid formation is the use of short peptides fragments as model systems. Short peptide fragments, as short as pentapeptides, were shown to form typical amyloid assemblies in vitro that have ultrastructural, biophysical, and cytotoxic properties, as those of assemblies that are being formed by full length polypeptides. When we analyzed such short fragments, we identified the central role of aromatic moieties in the ability to aggregate into ordered nano-fibrillar structures. This notion allowed us to discover additional very short amyloidogenic peptides as well as other aromatic peptide motifs, which can form various assemblies at the nano-scale (including nanotubes, nanospheres, and macroscopic hydrogels with nano-scale order). Other practical utilization of this concept, together with novel β breakage methods, is their use for the development of novel classes of amyloid formation inhibitors.

Key Words: Alzheimer's disease, amyloid disease, molecular recognition, nanostructures, protein aggregation, protein misfolding, self-assembly, type II diabetes

The Ultrastructural and Physiological Properties of Amyloid Fibrils

The formation of amyloid protein deposition is associated with major human diseases. A partial list includes Alzheimer's disease, Parkinson's disease, Type II diabetes, Prion disorders and many more.1–3 There are more than twenty human disorders that are associated with the formation of amyloid fibrils. In all these cases, fibrillar assemblies that have a diameter of 7–10 nm are being observed by electron microscopy (EM) or atomic force microscopy (AFM).1–3 The amyloid fibrils are well-ordered assemblies that have a typical 4.6–4.8 Å X-ray fiber diffraction reflection on the meridian. This reflection is consistent with high degree of order along the long-axis of the fibrils. The order of the fibrils is also reflected in their typical green-gold birefringence when examined between cross-polarizers upon staining with the Congo Red dye. The process of formation of well-ordered amyloid fibrils was depicted as ”one dimensional crystallization“ by Peter Lansbury and coworkers.4

Amyloid assemblies also show a predominant β sheet structure as shown by circular dichroism (CD) and Fourier-transformed infrared (FTIR) spectroscopy. This secondary structure nicely correlates with the well-ordered X-ray fiber diffraction pattern as the stacking of β strand (as observed in other elongated biological assemblies such as silk and β helix protein) is consistent with those parameters. This secondary structure is also a key feature that is being used to inhibit amyloid formation by the use of β breaker elements as will be further described here. A very interesting point is that fibrils of different origins (e.g., from the brain of Alzheimer's disease patients and the pancreas of individuals affected with Type II diabetes) show remarkable biophysical and ultrastructural properties as described above. However, despite the remarkable similarity, no simple homology between the amyloid-forming proteins is apparent.

Do Amyloid Fibrils Represent the True Pathological Assemblies?

Although fibrillar amyloid assemblies are identified in various amyloid diseases, it is not clear whether these are the genuine pathological species in those disorders. Recent studies suggested that actually early soluble oligomeric assemblies, rather than mature fibrils, may represent the pathological agents in various amyloid disorders (Fig. 1).5–18 The most studied system is that of Alzheimer's disease β amyloid polypeptide in which small soluble assemblies appeared to be correlated with memory impairment in cellular and rodent models.5,15,17–18 The in vivo detection of soluble oligomeric assemblies occurs well before the detection of amyloid deposits and it is correlated with impairment. Indeed soluble assemblies, such as the dodecameric Aβ*56 (Fig. 1), were found to directly affect the process of long-term potentiation (LTP), a synaptic activity that is associated with memory and learning.17–18

Figure 1.

Figure 1

Open in a new tab

The molecular cascade that leads to the formation of amyloid fibrils. The formation of amyloid fibrils is a sequential process that proceeds from monomeric species into well-ordered amyloid fibrils. It is still unclear whether the formation of soluble oligomers such as the Aβ*5617 and the annular amyloid pores,8 is an on-pathway or an off-pathway process.

The new appreciation for the role of early oligomers in amyloid-associated disease pathology clearly suggests that very early events of amyloid formation should be inhibited. Therefore the early molecular recognition and self-assembly processes should be marked as the key target for the development of therapeutic agents that could control the formation of the pathological species. The genuine understanding of the molecular interfaces that mediate recognition and association is consequently critical for future pharmacological developments.

The Use of Peptide Models to Study the Mechanism of Amyloid Formation

While amyloid fibrils are being formed in most cases by polypeptides of 30–40 amino acids or even longer, other studies had demonstrated that peptide fragments, as short as hexapeptides, form amyloid fibrils of similar physical and ultrastructural properties as described above.19–23 The first hexapeptide system that was studied is the NFGAIL amyloid-forming peptide fragment from the islet amyloid polypeptide (IAPP).19 This peptide was found to assemble into typical amyloid fibrils that show the ultrastructure, molecular conformation, and cytotoxicity that are similar to that of amyloid deposits that are formed by the full-length polypeptide.19

To decipher the mechanism of amyloid formation, we systematically analyzed short peptide fragments to pinpoint residues that play a role in the molecular recognition and self-assembly process. In the first experimental system, a short amyloid forming motif from the diabetes-related IAPP was studied.24 Using a systematic alanine scan, we identified the key role of phenylalanine in the NFGAILSS motif (Fig. 2).24 It was revealed that any amino-acid, but the phenylalanine, could be substituted to an alanine and a significant level of formation of amyloid fibrils would still be detected (Fig. 2).24 Only when the phenylalanine was change to an alanine, no amyloid formation could be observed under the experimental conditions. When vertical scan of this peptide fragment was made, it was found that modification of the phenylalanine into aliphatic amino acids significantly reduced the ability of the peptide to form typical amyloid fibrils.25 On the other hand modification of the phenylalanine to tryptophan (that is less hydrophobic than phenylalanine) allows the formation of amyloid-like structure (Fig. 2).26 In a later study by Dobson and coworkers, in which the amyloidogenic propensity of all naturally occurring amino acids was compared, aromatic amino acids were determined to have the highest amyloid forming propensity.27 The amyloidogenic potential of the aromatic amino acid is significantly higher than that of the aliphatic ones.

Figure 2.

Figure 2

Open in a new tab

Systematic study of amyloid formation. Alanine scan was first used to identify the phenylalanine as the most important residue in amyloid formation by this fragment. This was followed by vertical scan in which the role of aromatic as compared to aliphatic residues was revealed.

Based on the mechanistic insights, we identified novel fragments, as short as tetrapeptides, which could form amyloid-like nano-structures. The two notable systems are the human calcitonin that forms amyloid assemblies in the case of thyroid carcinoma22 and the ubiquitous Medin deposits.23 In the first case, the known information was the pH-dependence of the process of amyloid formation by the full length Calcitonin polypeptide.22 This suggested that charged amino-acids, that can change their ionization-state in various pH conditions, may have a role in the process of amyloid formation. These led to the exploration of short charged-aromatic DFNKF pentapeptide and DFNK tetrapeptide fragments that can form ordered fibrillar structures.22 While the pentapeptide formed typical amyloid fibrils, the fibrils formed by the tetrapeptide showed somewhat thicker diameter. In the other study the amyloidogenic potential of a hexapeptide fragment of human medin, a protein that forms amyloid deposits that is observed practically in all individuals above the age of 60. The aromatic hexapeptide, NFGSVQ, formed typical amyloid structures with the ultrastructural and biophysical properties as described above.23 Also in the case of the calcitonin and medin fragments, the change of the phenylalanine reside to aliphatic residues significantly reduced the level of amyloid formation.22–23

While the amyloidogenic potential of the aromatic moieties is well appreciated there is still a debate regarding the molecular mechanism of their action. We previously suggested that stacking interactions of aromatic moieties may be the root for their ability to efficiently mediate the formation of amyloid fibrils.28 The order and directionally of π-π stacking interactions was suggested as a driving force for the efficient formation of ordered amyloid assemblies.28 Indeed, in several structural studies of amyloid assemblies, typical aromatic interactions were being observed at high resolution using NMR, X-ray, and electron diffraction.29–32 In addition also theoretical studies, including parameter-free models and molecular dynamics, support this notion.33–37 Yet, other studies had indicated that properties of the aromatic moieties, other than their stacking interactions, may be the root for their activity at least in some systems.38 We hope that further studies will help to give better answer to this important scientific quest.

The Self-Assembly of Shorter Aromatic Peptides

The calcitonin study was the first demonstration that a peptide, as short as a tetrapeptide, can form ordered fibrillar structures. Similar to the calcitonin work, we identified very short amyloidogenic motifs in many other amyloid-forming proteins and polypeptides. In our path to search for the smallest amyloidogenic structural motif, we studied the core recognition motif of the Alzheimer's β amyloid peptide. We revealed that the diphenylalanine peptide forms discrete and well-ordered tubular nanostructures.39 The formed nanotubes may share some structural properties with the amyloid fibrils as they have similar vibrational spectrum and birefringence as compared to the fibrils. The even simpler diphenylglycine peptide forms nano-spherical assemblies which are similar to the tubular ones.40 This indicates that the very simple dipeptide aromatic motifs contain all the molecular information needed to form well-ordered supramolecular structures at the nano-scale.

Later studies from our group reveled that other aromatic homo-dipeptides could form various structures at the nano-scale. The structures included, besides nanotubes and nanospheres, also fibrillar assemblies, nano-plates and hydrogels with nano-scale order.41–43 These structures are currently being explored for their utilization in various nanotechnological applications.44–45

Inhibition of Amyloid Formation by Peptide Fragments

We explored various directions towards the use of aromatic amino acids in the process of self-assembly at the nano-scale level, and particularly amyloid formation, to develop novel amyloid formation inhibitors. The aromatic moieties represent recognition interfaces that mediate the very early stage of amyloid formation. We utilize both peptide-based26 and small-molecule-based46–47 approaches to develop new inhibitors for the process of amyloid formation at its very early stage. When peptide inhibitors are being used, we utilize the novel inhibitory strategy that is based on the use of the α-aminoisobutyric acid as a β breaker of exceptional potency.48

Summary and Future Prospects

Amyloid nanofibers are naturally occurring self-assembled biological structures. Aromatic moieties play a central role in amyloid fibrils self-assembly by extremely short peptides. We speculate that the stacking interactions rather than mere hydrophobicity may provide energetic contribution as well as order and directionality in the self-assembly of amyloid structures. The hypothesis suggests a new approach to understand the self-assembly mechanism, enables the identification of novel motifs, and indicates new ways to control this process.

Footnotes

Previously published online as a Prion E-publication: http://www.landesbioscience.com/journals/Prion/abstract.php?id=4095

References

  • 1.Rochet JC, Lansbury PT., Jr Amyloid fibrillogenesis: Themes and variations. Curr Opin Struct Biol. 2000;10:60–68. doi: 10.1016/s0959-440x(99)00049-4. [DOI] [PubMed] [Google Scholar]
  • 2.Makin OS, Serpell LC. Structures for amyloid fibrils. FEBS J. 2005;272:5950–5961. doi: 10.1111/j.1742-4658.2005.05025.x. [DOI] [PubMed] [Google Scholar]
  • 3.Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem. 2006;75:333–366. doi: 10.1146/annurev.biochem.75.101304.123901. [DOI] [PubMed] [Google Scholar]
  • 4.Jarrett JT, Lansbury PT., Jr Seeding ”one-dimensional crystallization“ of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? Cell. 1993;73:1055–1058. doi: 10.1016/0092-8674(93)90635-4. [DOI] [PubMed] [Google Scholar]
  • 5.Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002;416:535–539. doi: 10.1038/416535a. [DOI] [PubMed] [Google Scholar]
  • 6.Klein WL. Aβ toxicity in Alzheimer's disease: Globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem Int. 2002;41:345–352. doi: 10.1016/s0197-0186(02)00050-5. [DOI] [PubMed] [Google Scholar]
  • 7.Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ. The formation of highly soluble oligomers of α-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron. 2003;37:583–595. doi: 10.1016/s0896-6273(03)00024-2. [DOI] [PubMed] [Google Scholar]
  • 8.Caughey B, Lansbury PT. Protofibrils pores, fibrils, and neurodegeneration: Separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003;26:267–298. doi: 10.1146/annurev.neuro.26.010302.081142. [DOI] [PubMed] [Google Scholar]
  • 9.Porat Y, Kolusheva S, Jelinek R, Gazit E. The human islet amyloid polypeptide forms transient membrane-active pre-fibrillar assemblies. Biochemistry. 2003;42:10971–10977. doi: 10.1021/bi034889i. [DOI] [PubMed] [Google Scholar]
  • 10.Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003;300:486–489. doi: 10.1126/science.1079469. [DOI] [PubMed] [Google Scholar]
  • 11.Glabe CG, Kayed R. Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis. Neurology. 2006;66:S74–S78. doi: 10.1212/01.wnl.0000192103.24796.42. [DOI] [PubMed] [Google Scholar]
  • 12.Malmo C, Vilasi S, Iannuzzi C, Tacchi S, Cametti C, Irace G, Sirangelo I. Tetracycline inhibits W7FW14F apomyoglobin fibril extension and keeps the amyloid protein in a prefibrillar, highly cytotoxic state. FASEB J. 2006;20:346–347. doi: 10.1096/fj.05-4652fje. [DOI] [PubMed] [Google Scholar]
  • 13.Bucciantini M, Calloni G, Chiti F, Formigli L, Nosi D, Dobson CM, Stefani M. Prefibrillar amyloid protein aggregates share common features of cytotoxicity. J Biol Chem. 2004;279:31374–31382. doi: 10.1074/jbc.M400348200. [DOI] [PubMed] [Google Scholar]
  • 14.Baglioni S, Casamenti F, Bucciantini M, Luheshi LM, Taddei N, Chiti F, Dobson CM, Stefani M. Prefibrillar amyloid aggregates could be generic toxins in higher organisms. J Neurosci. 2006;26:8160–8167. doi: 10.1523/JNEUROSCI.4809-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer's amyloid b-peptide. Nat Rev Mol Cell Biol. 2007;8:101–112. doi: 10.1038/nrm2101. [DOI] [PubMed] [Google Scholar]
  • 16.Necula M, Kayed R, Milton S, Glabe CG. Small-molecule inhibitors of aggregation indicate that amyloid β oligomerization and fibrillization pathways are independent and distinct. J Biol Chem. 2007 doi: 10.1074/jbc.M608207200. In press. [DOI] [PubMed] [Google Scholar]
  • 17.Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-β protein assembly in the brain impairs memory. Nature. 2006;440:352–357. doi: 10.1038/nature04533. [DOI] [PubMed] [Google Scholar]
  • 18.Barghorn S, Nimmrich V, Striebinger A, Krantz C, Keller P, Janson B, Bahr M, Schmidt M, Bitner RS, Harlan J, Barlow E, Ebert U, Hillen H. Globular amyloid β-peptide oligomer—A homogenous and stable neuropathological protein in Alzheimer's disease. J Neurochem. 2005;95:834–847. doi: 10.1111/j.1471-4159.2005.03407.x. [DOI] [PubMed] [Google Scholar]
  • 19.Tenidis K, Waldner M, Bernhagen J, Fischle W, Bergmann M, Weber M, Merkle ML, Voelter W, Brunner H, Kapurniotu A. Identification of a penta- and hexapeptide of islet amyloid polypeptide (IAPP) with amyloidogenic and cytotoxic properties. J Mol Biol. 2000;295:1055–1071. doi: 10.1006/jmbi.1999.3422. [DOI] [PubMed] [Google Scholar]
  • 20.Balbach JJ, Ishii Y, Antzutkin ON, Leapman RD, Rizzo NW, Dyda F, Reed J, Tycko R. Amyloid fibril formation by Aβ 16–22, a seven-residue fragment of the Alzheimer's β-amyloid peptide, and structural characterization by solid state NMR. Biochemistry. 2000;39:13748–13759. doi: 10.1021/bi0011330. [DOI] [PubMed] [Google Scholar]
  • 21.Mazor Y, Gilead S, Benhar I, Gazit E. Identification and characterization of a novel molecular- recognition and self-assembly domain within the islet amyloid polypeptide. J Mol Biol. 2002;322:1013–1024. doi: 10.1016/s0022-2836(02)00887-2. [DOI] [PubMed] [Google Scholar]
  • 22.Reches M, Porat Y, Gazit E. Amyloid fibril formation by pentapeptide and tetrapeptide fragments of human calcitonin. J Biol Chem. 2002;277:35475–35480. doi: 10.1074/jbc.M206039200. [DOI] [PubMed] [Google Scholar]
  • 23.Reches M, Gazit E. Amyloidogenic hexapeptide fragment of medin: Homology to functional islet amyloid polypeptide fragments. Amyloid. 2004;11:81–89. doi: 10.1080/13506120412331272287. [DOI] [PubMed] [Google Scholar]
  • 24.Azriel R, Gazit E. Analysis of the minimal amyloid-forming fragment of the islet amyloid polypeptide: An experimental support for the key role of the phenylalanine residue in amyloid formation. J Biol Chem. 2001;276:34156–34161. doi: 10.1074/jbc.M102883200. [DOI] [PubMed] [Google Scholar]
  • 25.Porat Y, Mazor Y, Efrat S, Gazit E. Inhibition of islet amyloid polypeptide fibril formation: A potential role for heteroaromatic interactions. Biochemistry. 2004;43:14454–14462. doi: 10.1021/bi048582a. [DOI] [PubMed] [Google Scholar]
  • 26.Porat Y, Stepensky A, Ding FX, Naider F, Gazit E. Completely different amyloidogenic potential of nearly identical peptide fragments. Biopolymers. 2003;69:161–164. doi: 10.1002/bip.10386. [DOI] [PubMed] [Google Scholar]
  • 27.Pawar AP, Dubay KF, Zurdo J, Chiti F, Vendruscolo M, Dobson CM. Prediction of ”aggregation-prone“ and ”aggregation-susceptible“ regions in proteins associated with neurodegenerative diseases. J Mol Biol. 2005;350:379–392. doi: 10.1016/j.jmb.2005.04.016. [DOI] [PubMed] [Google Scholar]
  • 28.Gazit E. A possible role for π-stacking in the self-assembly of amyloid fibrils. FASEB J. 2002;16:77–83. doi: 10.1096/fj.01-0442hyp. [DOI] [PubMed] [Google Scholar]
  • 29.Naito A, Kamihira M, Inoue R, Saito H. Structural diversity of amyloid fibril formed in human calcitonin as revealed by site-directed 13C solid-state NMR spectroscopy. Magn Reson Chem. 2004;42:247–257. doi: 10.1002/mrc.1323. [DOI] [PubMed] [Google Scholar]
  • 30.Makin OS, Atkins E, Sikorski P, Johansson J, Serpell LC. Molecular basis for amyloid fibril formation and stability. Proc Natl Acad Sci USA. 2005;102:315–320. doi: 10.1073/pnas.0406847102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Inouye H, Sharma D, Goux WJ, Kirschner DA. Structure of core domain of fibril-forming PHF/Tau fragments. Biophys J. 2006;90:1774–1789. doi: 10.1529/biophysj.105.070136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Colombo G, Daidone I, Gazit E, Amadei A, Di Nola A. Molecular dynamics simulation of the aggregation of the core-recognition motif of the islet amyloid polypeptide in explicit water. Proteins. 2005;59:519–527. doi: 10.1002/prot.20426. [DOI] [PubMed] [Google Scholar]
  • 33.Jack E, Newsome M, Stockley PG, Radford SE, Middleton DA. The organization of aromatic side groups in an amyloid fibril probed by solid-state 2H and 19F NMR spectroscopy. J Am Chem Soc. 2006;128:8098–8099. doi: 10.1021/ja0581898. [DOI] [PubMed] [Google Scholar]
  • 34.Tartaglia GG, Cavalli A, Pellarin R, Caflisch A. The role of aromaticity, exposed surface, and dipole moment in determining protein aggregation rates. Protein Sci. 2004;13:1939–1941. doi: 10.1110/ps.04663504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Haspel N, Zanuy D, Ma B, Wolfson H, Nussinov R. A comparative study of amyloid fibril formation by residues 15–19 of the human calcitonin hormone: A single β-sheet model with a small hydrophobic core. J Mol Biol. 2005;345:1213–1227. doi: 10.1016/j.jmb.2004.11.002. [DOI] [PubMed] [Google Scholar]
  • 36.Wu C, Lei H, Duan Y. The role of Phe in the formation of well-ordered oligomers of amyloidogenic hexapeptide (NFGAIL) observed in molecular dynamics simulations with explicit solvent. Biophys J. 2005;88:2897–2906. doi: 10.1529/biophysj.104.055574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Caflisch A. Computational models for the prediction of polypeptide aggregation propensity. Curr Opin Chem Biol. 2006;10:437–444. doi: 10.1016/j.cbpa.2006.07.009. [DOI] [PubMed] [Google Scholar]
  • 38.Bemporad F, Taddei N, Stefani M, Chiti F. Assessing the role of aromatic residues in the amyloid aggregation of human muscle acylphosphatase. Protein Sci. 2006;15:862–870. doi: 10.1110/ps.051915806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Reches M, Gazit E. Casting metal nanowires within discrete self-assembled peptide nano-tubes. Science. 2003;300:625–627. doi: 10.1126/science.1082387. [DOI] [PubMed] [Google Scholar]
  • 40.Reches M, Gazit E. Formation of closed-cage nanostructures by self-assembly of aromatic dipeptides. Nano Lett. 2004;4:581–585. [Google Scholar]
  • 41.Reches M, Gazit E. Self-assembly of peptide nanotubes and amyloid-like structures by charged-termini capped diphenylalanine peptide analogues. Israel J Chem. 2005;45:363–371. [Google Scholar]
  • 42.Reches M, Gazit E. Designed aromatic homo-dipeptides: Formation of ordered nanostructures and potential nanotechnological applications. Phys Biol. 2006;3:S10–S19. doi: 10.1088/1478-3975/3/1/S02. [DOI] [PubMed] [Google Scholar]
  • 43.Mahler A, Reches M, Rechter M, Cohen S, Gazit E. Rigid, self-assembled hydrogel composed of a modified aromatic dipeptide. Adv Mater. 2006;18:1365–1370. [Google Scholar]
  • 44.Yemini M, Reches M, Rishpon J, Gazit E. Novel electrochemical biosensing platform using self-assembled peptide nanotubes. Nano Lett. 2005;5:183–186. doi: 10.1021/nl0484189. [DOI] [PubMed] [Google Scholar]
  • 45.Reches M, Gazit E. Controlled patterning of aligned self-assembled peptide nanotubes. Nat Nanotech. 2006;1:195–200. doi: 10.1038/nnano.2006.139. [DOI] [PubMed] [Google Scholar]
  • 46.Cohen T, Frydman-Marom A, Rechter M, Gazit E. Inhibition of amyloid fibril formation and cytotoxicity by hydroxyindole derivatives. Biochemistry. 2006;45:4727–4735. doi: 10.1021/bi051525c. [DOI] [PubMed] [Google Scholar]
  • 47.Porat Y, Abramowitz A, Gazit E. Inhibition of amyloid fibril formation by polyphenols: Structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des. 2006;67:27–37. doi: 10.1111/j.1747-0285.2005.00318.x. [DOI] [PubMed] [Google Scholar]
  • 48.Gilead S, Gazit E. Inhibition of amyloid fibril formation by peptide analogues modified with a-aminoisobutyric acid. Angew Chem Int Ed Engl. 2004;43:4041–4044. doi: 10.1002/anie.200353565. [DOI] [PubMed] [Google Scholar]

Articles from Prion are provided here courtesy of Taylor & Francis

RESOURCES