School of Medicine and Surgery, University of Milano-Bicocca, Vedano al Lambro, Italy.
Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Pavia, Italy.
Ann Med. 2023 Dec;55(1):2205659. doi: 10.1080/07853890.2023.2205659.
The effect of liposomes bi-functionalized with phosphatidic acid and with a synthetic peptide derived from human apolipoprotein E has been evaluated on the aggregation features of different amyloidogenic proteins: human Amyloid β1-40 (Aβ), transthyretin (TTR) variant S52P, human β2microglobulin (β2m) variants ΔN6 and D76N, Serum Amyloid A (SAA).
The formation of fibrillar aggregates of the proteins was investigated by ThioflavinT fluorescence assay and validated by Atomic Force Microscopy.
The results show that liposomes are preventing the transition of non-aggregated forms to the fibrillar state, with stronger effects on Aβ, β2m ΔN6 and SAA. Liposomes also induce disaggregation of the amyloid aggregates of all the proteins investigated, with stronger effects on Aβ, β2 D76N and TTR.SPR assays show that liposomes bind Aβ and SAA aggregates with high affinity (KD in the nanomolar range) whereas binding to TTR aggregates showed a lower affinity (KD in the micromolar range). Aggregates of β2m variants showed both high and low affinity binding sites. Computed Structural analysis of protein fibrillar aggregates and considerations on the multidentate features of liposomes allow to speculate a common mechanism of action, based on binding the β-stranded peptide regions responsible for the amyloid formation.
Thus, multifunctional liposomes perform as pharmacological chaperones with anti-amyloidogenic activity, with a promising potential for the treatment of a number of protein-misfolding diseases.Key messageAmyloidosis is a group of diseases, each due to a specific protein misfolding.Anti-amyloidogenic nanoparticles have been gaining the utmost importance as a potential treatment for protein misfolding disorders.Liposomes bi-functionalized with phosphatidic acid and with a synthetic peptide derived from human apolipoprotein E showed anti-amyloidogenic activity.
评估同时具有磷脂酸和源自人载脂蛋白 E 的合成肽的脂质体对不同淀粉样蛋白原蛋白聚集特性的影响：人淀粉样蛋白 β1-40（Aβ）、转甲状腺素蛋白（TTR）变体 S52P、人β2 微球蛋白（β2m）变体 ΔN6 和 D76N、血清淀粉样蛋白 A（SAA）。
通过硫黄素 T 荧光测定法研究蛋白质的纤维状聚集物的形成，并通过原子力显微镜进行验证。
结果表明，脂质体可防止无聚集形式向纤维状态的转变，对 Aβ、β2m ΔN6 和 SAA 的作用更强。脂质体还诱导所有研究的蛋白质的淀粉样聚集物的解聚，对 Aβ、β2 D76N 和 TTR 的作用更强。SPR 测定表明，脂质体以高亲和力（纳摩尔范围内的 KD）结合 Aβ 和 SAA 聚集物，而与 TTR 聚集物的结合亲和力较低（微摩尔范围内的 KD）。β2m 变体的聚集物均显示出高亲和和低亲和结合位点。基于对蛋白纤维状聚集物的结构分析和对脂质体的多齿特征的考虑，可以推测出一种共同的作用机制，基于结合负责淀粉样形成的β-折叠肽区域。
因此，多功能脂质体作为具有抗淀粉样形成活性的药理学伴侣，具有治疗多种蛋白错误折叠疾病的巨大潜力。
淀粉样变性是一组疾病，每种疾病都由特定的蛋白质错误折叠引起。抗淀粉样形成纳米颗粒作为蛋白错误折叠疾病的潜在治疗方法越来越受到重视。同时具有磷脂酸和源自人载脂蛋白 E 的合成肽的脂质体表现出抗淀粉样形成活性。
