cis-γ-Amino-L-proline peptides as chemical probes of amyloidogenic processing in neurons and APP/PS1 mice

Abstract

Abstract Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides, which are a key factor in its pathogenesis. In this study, we present the design and evaluation of γ-amino-L-proline peptides as metabolically stable, cell-penetrating molecules that can modulate amyloidogenic processing. We screened a library of γ-peptides in primary neuronal cultures to determine their effects on endogenous Aβ1-42 production, cytotoxicity, and β-secretase (BACE1) activity. Comparative analysis of structurally related analogues enabled the identification of molecular features associated with Aβ-lowering activity, establishing a qualitative structure–activity relationship. Peptide 33 ( P33 ) emerged as a lead candidate, selectively reducing BACE1 activity without significantly inhibiting the homologous enzyme, BACE2. In vitro blood-brain barrier (BBB) assays revealed that P33 exhibits favorable transendothelial permeability. Intraperitoneal administration of P33 in APP/PS1 mice decreased Aβ levels, reduced amyloid plaque burden, and improved performance in a behavioral recognition task without inducing cytotoxicity or systemic toxicity. These results define cis-γ-amino-L-proline peptides as a bioorganically distinct and modular scaffold for the development of intracellular modulators of Aβ production. Highlights γLJAminoLJLLJproline peptides as metabolically stable modulators of Aβ production. P33 showed BBB permeability and BACE1 inhibition in primary cortical neurons. In APP/PS1 mice, P33 lowers amyloid burden and improves cognition. P33 shows good biocompatibility, supporting its therapeutic potential in AD