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

Alzheimers disease (AD) is characterized by the accumulation of amyloid-{beta} (A{beta}) peptides, which are a key factor in its pathogenesis. In this study, we present the design and evaluation of {gamma}-amino-L-proline peptides as metabolically stable, cell-penetrating molecules that can modulate amyloidogenic processing. We screened a library of {gamma}-peptides in primary neuronal cultures to determine their effects on endogenous A{beta}1-42 production, cytotoxicity, and {beta}-secretase (BACE1) activity. Comparative analysis of structurally related analogues enabled the identification of molecular features associated with A{beta}-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 A{beta} levels, reduced amyloid plaque burden, and improved performance in a behavioral recognition task without inducing cytotoxicity or systemic toxicity. These results define cis-{gamma}-amino-L-proline peptides as a bioorganically distinct and modular scaffold for the development of intracellular modulators of A{beta} production. HighlightsO_LI{gamma}LJAminoLJLLJproline peptides as metabolically stable modulators of A{beta} production. C_LIO_LIP33 showed BBB permeability and BACE1 inhibition in primary cortical neurons. C_LIO_LIIn APP/PS1 mice, P33 lowers amyloid burden and improves cognition. C_LIO_LIP33 shows good biocompatibility, supporting its therapeutic potential in AD C_LI