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The modulation of protein aggregation is involved not only in biochemical engineering processes, but also in in vivo biological events such as Alzheimer’s disease (AD) that features amyloid-β protein (Aβ) deposits. Inspired by the different pharmacological efficacy of enantiomers, taking heptapeptide LVFFARK (LK7) as an example, herein the chiral influence of peptide inhibitors on Aβ fibrillogenesis and cytotoxicity was investigated by extensive biophysical and biological analyses. It was intriguing to find that although both L- LK7 and D- LK7 could inhibit Aβ aggregation in a concentration-dependent manner, it was the d- enantiomer that exhibited chirality preference and selectivity for modulation of Aβ self-assembly. As compared with L- LK7 at the same conditions, D- LK7 showed significantly enhanced potency on suppressing cross-β sheet formation, fibrillar Aβ aggregates deposition, Aβ conformational transition, and Aβ-triggered neurotoxicity on cultured cells. For instance, L- LK7 and D- LK7 rescued cells by increasing cell viability from 60% to 62% and 84% at 100 μmol·L−1, respectively. The chiral discrimination of L-LK7 and D- LK7 was further validated by the different elimination efficiency on amyloid accumulation in AD model nematodes. It is considered that the higher binding affinity of D- LK7 to Aβ monomers than that of L- LK7 resulted in the stronger inhibition effect. This work provided new insights into understanding chirality in the interaction with Aβ and the consequent inhibitory effect, and would contribute to the design of anti-amyloid agents. |
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