Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation

Kroth, Heiko; Ansaloni, Annalisa; Varisco, Yvan; Jan, Asad; Sreenivasachary, Nampally; Rezaei‐Ghaleh, Nasrollah; Giriens, Valérie; Lohmann, Sophie; López-Deber, María Pilar; Adolfsson, Oskar; Pihlgren, Maria; Paganetti, Paolo; Froestl, Wolfgang; Nagel-Steger, Luitgard; Willbold, Dieter; Schräder, Thomas; Zweckstetter, Markus; Pfeifer, Andrea; Lashuel, Hilal A.; Muhs, Andreas

doi:10.1074/jbc.m112.357665

Cited by 57 publications

(50 citation statements)

References 71 publications

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“…Thus, we conclude that the structural transformation of the hydrophobic patch of TDP-43 triggers its misfolding, aggregation, and cytoplasmic inclusion formation, which are implicated in disease pathology (44). This particular core region may provide a potential target to design small-molecule compounds that can interfere with ␣-to-␤ structural transformation for therapeutic treatment of the TDP-43 proteinopathies (45,46).…”

Section: Discussionmentioning

confidence: 83%

Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion

Jiang

Xia

Zhao

et al. 2013

Journal of Biological Chemistry

144

190

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Background:The highly flexible C-terminal region of TDP-43 is implicated in disease pathology. Results: An amyloidogenic core was identified to be critical for TDP-43 aggregation. Conclusion: Helix-to-sheet structural transformation of the amyloidogenic core initiates TDP-43 aggregation and cytoplasmic inclusion formation. Significance: This is a potential therapeutic target for mitigating the TDP-43 proteinopathies.

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Section: Discussionmentioning

confidence: 83%

Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion

Jiang

Xia

Zhao

et al. 2013

Journal of Biological Chemistry

144

190

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“…These data suggest that the monomeric Aβ 42 may also have a high propensity for β-sheet formation in aqueous solution even though the main secondary structure for the peptide is a coil. As a consequence of the high aggregation properties of Aβ (and Aβ 42 in particular) as well as the cytotoxicity of Aβ oligomers, there is tremendous interest in preventing Aβ aggregation by identifying inhibitors of Aβs [37][38][39] . Various inhibitors, such as antibodies, small compounds, Chinese herbal medicines, and peptides, have been explored in the prevention of Aβ aggregation [37,38,[40][41][42] .…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence of the high aggregation properties of Aβ (and Aβ 42 in particular) as well as the cytotoxicity of Aβ oligomers, there is tremendous interest in preventing Aβ aggregation by identifying inhibitors of Aβs [37][38][39] . Various inhibitors, such as antibodies, small compounds, Chinese herbal medicines, and peptides, have been explored in the prevention of Aβ aggregation [37,38,[40][41][42] . Sievers et al reported inhibitors against the amyloid fibril formation based on a steric zipper structure of an Aβ fragment (VQIVYK) where the D-aminoacid hexapeptide was designed via a computational method to interact with the fragment and to cap its fibril ends [37] .…”

Section: Discussionmentioning

confidence: 99%

“…Sievers et al reported inhibitors against the amyloid fibril formation based on a steric zipper structure of an Aβ fragment (VQIVYK) where the D-aminoacid hexapeptide was designed via a computational method to interact with the fragment and to cap its fibril ends [37] . Kroth et al discovered and designed a series of small compounds to inhibit the fibril formation of Aβs at μmol/L concentrations [38,43] . In addition, Jan-Philipp Bach and Richard Dodel reviewed the study of naturally occurring autoantibodies against β-amyloid that improve cognition in transgenic mice by interfering with oligomers of Aβ [40] .…”

Section: Discussionmentioning

confidence: 99%

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Microsecond molecular dynamics simulation of Aβ42 and identification of a novel dual inhibitor of Aβ42 aggregation and BACE1 activity

Wang

Chen

et al. 2013

Acta Pharmacol Sin

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Aim: To study the conformational changes of Aβ 42 and discover novel inhibitors of both Aβ 42 aggregation and β-secretase (BACE1). Methods: A molecular dynamics (MD) simulation at a microsecond level was performed to explore stable conformations of Aβ 42 monomer in aqueous solution. Subsequently, structure-based virtual screening was used to search for inhibitors of both Aβ 42 aggregation and BACE1. Protein purification and in vitro activity assays were performed to validate the inhibition of the compounds identified via virtual screening. Results: The initial α-helical conformation of Aβ 42 , which was unstable in aqueous solution, turned into a β-sheet mixed with a coil structure through a transient and fully random coil. The conformation of Aβ 42 mainly comprising β-sheets and coils structure was used for further virtual screening. Five compounds were identified as inhibitors for Aβ 42 aggregation, and one of them, AE-848, was discovered to be a dual inhibitor of both Aβ 42 aggregation and BACE1, with IC 50 values of 36.95 μmol/L and 22.70 μmol/L, respectively. Conclusion: A helical to β-sheet conformational change in Aβ 42 occurred in a 1.8 microsecond MD simulation. The resulting β-sheet structure of the peptide is an appropriate conformation for the virtual screening of inhibitors against Aβ 42 aggregation. Five compounds were identified as inhibitors of Aβ 42 aggregation by in vitro activity assays. It was particularly interesting to discover a dual inhibitor that targets both Aβ 42 aggregation and BACE1, the two crucial players in the pathogenesis of Alzheimer's disease.

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“…In vitro studies on these soluble cytotoxic oligomeric Aβ aggregates should provide a description of the fibril formation mechanism at the very early stages of aggregation 13 . Understanding why and how the peptide may adopt a non-native fold is essential for designing therapeutic approaches 14 . In view of these arguments, we chose to study Aβ42 aggregation.…”

Section: Introductionmentioning

confidence: 99%

Real-time protein aggregation monitoring with a Bloch surface wave-based approach

et al. 2014

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The misfolding and aggregation of amyloid proteins has been associated with incurable diseases such as Alzheimer's or Parkinson's disease. In the specific case of Alzheimer's disease, recent studies have shown that cell toxicity is caused by soluble oligomeric forms of aggregates appearing in the early stages of aggregation, rather than by insoluble fibrils. Research on new strategies of diagnosis is imperative to detect the disease prior to the onset of clinical symptoms. Here, we propose the use of an optical method for protein aggregation dynamic studies using a Bloch surface wave based approach. A one dimension photonic crystal made of a periodic stack of silicon oxide and silicon nitride layers is used to excite a Bloch surface wave, which is sensitive to variation of the refractive index of an aqueous solution. The aim is to detect the early dynamic events of protein aggregation and fibrillogenesis of the amyloid-beta peptide Aβ42, which plays a central role in the onset of the Alzheimer's disease. The detection principle relies on the refractive index changes caused by the depletion of the Aβ42 monomer concentration during oligomerization and fibrillization. We demonstrate the efficacy of the Bloch surface wave approach by monitoring in real-time the first crucial steps of Aβ42 oligomerization.

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Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation

Cited by 57 publications

References 71 publications

Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion

Structural Transformation of the Amyloidogenic Core Region of TDP-43 Protein Initiates Its Aggregation and Cytoplasmic Inclusion

Microsecond molecular dynamics simulation of Aβ42 and identification of a novel dual inhibitor of Aβ42 aggregation and BACE1 activity

Real-time protein aggregation monitoring with a Bloch surface wave-based approach

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