Repurposing Antimicrobial Protegrin-1 as a Dual-Function Amyloid Inhibitor via Cross-seeding
Repurposing Antimicrobial Protegrin-1 as a Dual-Function Amyloid Inhibitor via Cross-seeding
复制标题
通过交叉播种将抗菌 Protegrin-1 重新利用为双功能淀粉样蛋白抑制剂
DOI：
10.1021/acschemneuro.3c00293
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发表时间：
2023
影响因子：
5
通讯作者：
Zheng, Jie
中科院分区：
文献类型：
--
作者：
Tang, Yijing;Zhang, Dong;Zheng, Jie
淀粉样蛋白和抗微生物肽传统上被认为是具有不同生物学功能和靶点的不同家族。然而，某些淀粉样蛋白和抗菌肽具有共同的结构和功能特征，有助于神经退行性疾病的发展。β淀粉样蛋白（Aβ）的聚集和微生物感染是阿尔茨海默病（AD）中相互关联的病理因素。在这项研究中，我们提出并证明了一种新的抗菌肽protegrin-1（PG-1）的再利用策略，它表现出同时防止Aβ聚集和微生物感染的能力，在体外和体内。通过使用蛋白质、细胞和蠕虫试验的综合分析，我们揭示了PG-1对Aβ的多种功能，包括：（i）在PG-1/Aβ = 0.25：1的低摩尔比下完全抑制Aβ聚集，（ii）将预先形成的Aβ原纤维分解成无定形聚集体，（iii）减少Aβ诱导的SH-SY 5 Y细胞和转基因GMC 101线虫的细胞毒性，以及（iv）保留对P.A.的原始抗微生物活性，大肠杆菌，美国，和S.E.之间。在Aβ存在下的菌株。从机制上讲，PG-1的双重抗淀粉样蛋白和抗菌功能主要源于其通过构象相似的β折叠缔合与不同的Aβ种子（KD= 1.24-1.90 μM）的强结合。这项工作介绍了一种有前途的策略，重新利用抗菌肽作为淀粉样蛋白抑制剂，有效地针对AD中的多种病理途径。
Amyloids and antimicrobial peptides have traditionally been recognized as distinct families with separate biological functions and targets. However, certain amyloids and antimicrobial peptides share structural and functional characteristics that contribute to the development of neurodegenerative diseases. Specifically, the aggregation of amyloid-β (Aβ) and microbial infections are interconnected pathological factors in Alzheimer’s disease (AD). In this study, we propose and demonstrate a novel repurposing strategy for an antimicrobial peptide of protegrin-1 (PG-1), which exhibits the ability to simultaneously prevent Aβ aggregation and microbial infection both in vitro and in vivo. Through a comprehensive analysis using protein, cell, and worm assays, we uncover multiple functions of PG-1 against Aβ, including the following: (i) complete inhibition of Aβ aggregation at a low molar ratio of PG-1/Aβ = 0.25:1, (ii) disassembly of the preformed Aβ fibrils into amorphous aggregates, (iii) reduction of Aβ-induced cytotoxicity in SH-SY5Y cells and transgenic GMC101 nematodes, and (iv) preservation of original antimicrobial activity against P.A.,E.coli., S.A., and S.E. strains in the presence of Aβ. Mechanistically, the dual anti-amyloid and anti-bacterial functions of PG-1 primarily arise from its strong binding to distinct Aβ seeds (KD= 1.24–1.90 μM) through conformationally similar β-sheet associations. This work introduces a promising strategy to repurpose antimicrobial peptides as amyloid inhibitors, effectively targeting multiple pathological pathways in AD.