임동준 (고려대학교)

최태수 (고려대학교)

임동준 (고려대학교)

최태수 (고려대학교)

Recent achievements in Alzheimer’s disease (AD) therapy using antibodies that remove soluble amyloid-<i style="font-family: "Times New Roman", serif; font-size: 12pt; text-indent: 12pt;">β</i> (1–42) (A<i style="font-family: "Times New Roman", serif; font-size: 12pt; text-indent: 12pt;">β</i>42) aggregates highlights importance of A<i style="font-family: "Times New Roman", serif; font-size: 12pt; text-indent: 12pt;">β</i>42 assemblies as therapeutic targets. peptide inhibitors that block A<i style="font-family: "Times New Roman", serif; font-size: 12pt; text-indent: 12pt;">β</i>42 fibrillation represent a promising strategy for mitigating AD pathogenesis. However, the highly heterogeneous nature of A<i style="font-family: "Times New Roman", serif; font-size: 12pt; text-indent: 12pt;">β</i>42 weakens short peptides binding, thereby hindering their development as effective therapeutics. In this study, we topologically reprogrammed a peptide inhibitor to strengthen its interactions with A<i style="font-family: "Times New Roman", serif; font-size: 12pt; text-indent: 12pt;">β</i>42, guided by structural characterization of the target. Through theoretical screening and biochemical assays, we identified an optimal peptide scaffold inhibiting A<i style="font-family: "Times New Roman", serif; font-size: 12pt; text-indent: 12pt;">β</i>42 aggregation for further engineering. This scaffold was dimerized via a disulfide bond intended to form anti-parallel alignment.  The modified dimeric peptide inhibitor exhibited enhanced binding to A<i style="font-family: "Times New Roman", serif; font-size: 12pt; text-indent: 12pt;">β</i>42 through anti-parallel <i style="font-family: "Times New Roman", serif; font-size: 12pt; text-indent: 12pt;">β</i>-sheet formation, leading to improved suppression of A<i style="font-family: "Times New Roman", serif; font-size: 12pt; text-indent: 12pt;">β</i>42 aggregation and significant reduction in aggregate-induced cytotoxicity. These findings demonstrate a structure-based peptide design strategy targeting the pathogenic fibrillar aggregation of intrinsically disordered proteins.