Spinelli_2025_Bioorg.Med.Chem.Lett__130305

In this review, we provide a comprehensive analysis of the role of natural peptides-particularly those derived from amphibian skin secretions-as multitarget-directed ligands (MTDLs) in the context of Alzheimer's disease (AD). Given the multifactorial nature of AD, where cholinergic dysfunction intersects with amyloid-beta aggregation, tau hyperphosphorylation, oxidative stress, metal ion imbalance, and monoamine oxidase dysregulation, therapeutic strategies capable of modulating several pathological pathways simultaneously are urgently needed. We begin by revisiting the cholinergic hypothesis and its molecular and structural underpinnings, emphasizing the relevance of key binding sites such as the catalytic active site (CAS) and the peripheral anionic site (PAS) of cholinesterases. The central axis of this review lies in the exploration of naturally occurring peptides that have demonstrated dual or multiple activities against AD-related targets. We highlight our group's pioneering work on amphibian-derived peptides such as Hp-1971, Hp-1935, and BcI-1003, which exhibit non-competitive inhibition of AChE and BChE, MAO-B modulation, and antioxidant properties. Furthermore, we describe additional peptide-rich extracts and bioactive sequences from various amphibians and other animal or plant sources, expanding the landscape of natural molecules with neuroprotective potential. We also delve into peptide modification strategies-such as amino acid substitution, cyclization, D-amino acid incorporation, and terminal/side-chain functionalization-that have been employed to enhance peptide stability, blood-brain barrier permeability, and target affinity. These strategies not only improve the pharmacokinetic profiles of native peptides but also open the door for the rational design of next-generation peptide therapeutics. Overall, this review underscores the vast potential of natural peptides as scaffolds for the development of multifunctional agents capable of intervening in the complex cascade of Alzheimer's pathology.