Switchable photooxygenation catalysts that sense higher-order amyloid structures

Abstract

Proteins can misfold into amyloid structures that are associated with diseases; however, the same proteins often have important biological roles. To degrade selectively the amyloid form without affecting the fraction of functional protein is, therefore, an attractive goal. Here we report target-state-dependent photooxygenation catalysts that are active only when bound to the cross-β-sheet structure that is characteristic of pathogenic aggregated amyloid proteins. We show these catalysts can selectively oxygenate the amyloid form of amyloid β-protein (Aβ) 1-42 in the presence of non-amyloid off-target substrates. Furthermore, photooxygenation with a catalyst that bears an Aβ-binding peptide attenuated the Aβ pathogenicity in the presence of cells. We also show that selective photooxygenation is generally applicable to other amyloidogenic proteins (amylin, insulin, β2-microglobulin, transthyretin and α-synuclein) and does not affect the physiologically functional non-aggregate states of these proteins. This is the first report of an artificial catalyst that can be selectively and reversibly turned on and off depending on the structure and aggregation state of the substrate protein.

Carbon Nanodot‐Sensitized Modulation of Alzheimer's β‐Amyloid Self‐Assembly, Disassembly, and Toxicity

“…As presented in Figure S12a–c in the Supporting Information, 9,10‐diphenylanthracene (DPA), which loses its absorption property through reacting with 1 O 2 , showed a drastic decrease in its absorbance after coincubation with bPEI@CDs under illumination, indicating the enhancement of 1 O 2 generation with the duration of light irradiation time. Aβ residue oxidation by oxidants has been reported to alter Aβ aggregation kinetics, resulting in the suppression of Aβ aggregation pathway . Aβ peptide residues, such as methionine and histidine, are easily oxidized by H 2 O 2 to include hydrophilic oxygen atoms in the side chains according to the nuclear magnetic resonance analysis; therefore, the hydrophobicity of Aβ residues become weakened, inducing the destabilization and conformational deformation of the peptide backbone.…”

Metal–Organic Frameworks Harness Cu Chelating and Photooxidation Against Amyloid β Aggregation in Vivo

“…Currently, Aβ photooxidants can be divided into two categories: small molecules and nanoparticles . However, small molecules including thioflavin T derivatives, riboflavin, or porphyrin, are easily aggregated to decrease photooxidative efficiency . In addition, the short lifetime of singlet oxygen ( 1 O 2 ) (<200 ns) as well as the short diffusion distance of 1 O 2 (≈1 μm) also abate their efficiency.…”

“…Photooxygenationo fA b has emerged as an effective way to inhibitA b aggregation due to the spatiotemporal controllability of light and the ability to prevent Ab reassembly.C urrently,A b photooxidantsc an be divided into two categories:s mallm olecules [4, 10] and nanoparticles. [11] However,s mall molecules including thioflavin Td erivatives, [12] riboflavin, [4] or porphyrin, [10b] are easily aggregated to decreasep hotooxidativee fficiency. [13] In addition, the short lifetimeo fsinglet oxygen ( 1 O 2 )( < 200 ns) as wella st he short diffusion distance of 1 O 2 ( % 1 mm) [14] also abate their efficiency.M oreover, reactive oxygen species (ROS) can simultaneously destroy normalc ells and tissues.…”

“…These results comfirmed the Ab-targeting enrichment of LPFFD-modified Hf-MOFs. For ab etter understanding of the importance of Ab targeting, the percentageo fA b oxidation [12] by Hf-MOF and LPFFD-modifiedH f-MOFsw as compared by matrix-assisted laser desorptioni onization time-of-flightm ass spectrometry (Figure 3b). Both Hf-MOFsa nd LPFFD-modified Hf-MOFs can oxidize Ab under the same conditions.…”

Peptid‐basierte molekulare Strategien zum Einsatz bei Proteinfehlfaltung, Proteinaggregation und Zelldegeneration

“…Das Konzept könnte auch auf andere amyloide Polypeptide anwendbar sein. Allerdings ist seine Anwendbarkeit bei Amyloidkrankheiten noch unklar …”