Multiple Actions of H₂S-Releasing Peptides in Human β-Amyloid Expressing C. elegans

Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder characterized by the loss of cognitive function. A major challenge in treating this ailment fully is its multifactorial nature, as it is associated with effects like deposition of Aβ plaques, oxidative distress, inflammation of neuronal cells, and low levels of the neurotransmitter acetylcholine (ACh). In the present work, we demonstrate the design, synthesis, and biological activity of peptide conjugates by coupling a H₂S-releasing moiety to the peptides known for their Aβ antiaggregating properties. These conjugates release H₂S in a slow and sustained manner, due to the formation of self-assembled structures and delivered a significant amount of H₂S within Caenorhabditis elegans. These conjugates are shown to target multiple factors responsible for the progression of AD: notably, we observed reduction in oxidative distress, inhibition of Aβ aggregation, and significantly increased ACh levels in the C. elegans model expressing human Aβ.