Abstract / Summary
Abstract The aberrant self-assembly of amyloid β (Aβ) peptides into toxic oligomers is a central event in Alzheimer’s disease, motivating the development of molecular systems capable of modulating or degrading these species. Porphyrins and porphyrin−peptide bioconjugates have emerged as promising photoactive platforms due to their known ability to generate the highly oxidant singlet oxygen (1O2) upon light excitation. Still, the mechanisms underlying their oxidative effects on Aβ remain unclear. Here, we investigate the photophysical properties and the 1O2-mediated oxidation capability of two porphyrin−peptide conjugates, Ph-Pep and its Zn-metallated analogue ZnPh-Pep, both incorporating the Aβ recognition motif KLVFF. Steady-state and time-resolved spectroscopic studies reveal the good preservation of the photophysical and photochemical properties of the porphyrin chromophore units after their conjugation with the peptide appendage. Population of the long-lived triplet state of both compounds under visible-light excitation results in an effective generation of 1O2. High-resolution mass spectrometry shows that the 1O2 photogenerated by ZnPh-Pep induces extensive oxidation, yielding peroxidic and hydroperoxidic species, and provides evidence of partial Aβ42 degradation. In contrast, Ph-Pep leads to a rapid loss of detectable Aβ signal, suggesting the formation of higher-order aggregates rather than peptide cleavage. These distinct outcomes highlight the roles of Zn2+ coordination and peptide conjugation in modulating the 1O2-driven pathways. Overall, this study provides a mechanistic insight into designing photoactivatable porphyrin-based constructs capable of degrading or modulating toxic Aβ assemblies, opening intriguing prospects for light-mediated therapeutic strategies for neurodegenerative diseases.