Bera Tapas, Saha Pranab Chandra, Chatterjee Tanima, Kar Samiran, Guha Samit
Department of Chemistry, Organic Chemistry Section, Jadavpur University, Kolkata 700032, India.
Department of Biochemistry, University of Calcutta, Kolkata 700019, India.
Bioconjug Chem. 2022 Jun 15;33(6):1201-1209. doi: 10.1021/acs.bioconjchem.2c00149. Epub 2022 May 17.
Alzheimer's disease, a progressive severe neurodegenerative disorder, has been until now incurable, in spite of serious efforts worldwide. We have designed self-assembled myristoyl-KPGPK lipopeptide-based biocompatible nanovesicles, which can inhibit amyloid fibrillation made by the transmembrane GxxxGxxxGxxxG motif of Aβ-protein and human myelin protein zero as well as reduce their neurotoxicity. Various spectroscopic and microscopic investigations illuminate that the lipopeptide-based nanovesicles dramatically inhibit random coil-to-β-sheet transformation of Aβ and human myelin protein zero protein precursor, which is the prerequisite of GxxxGxxxGxxxG motif-mediated fibril formation. Förster resonance energy transfer (FRET) assay using synthesized Cy-3 (FRET donor) and Cy-5 (FRET acceptor)-conjugated Aβ also exhibits that nanovesicles strongly inhibit the fibril formation of Aβ. The mouse neuro-2a neuroblastoma cell line is used, which revealed the GxxxGxxxGxxxG-mediated cytotoxicity. However, the neurotoxicity has been diminished by co-incubating the GxxxGxxxGxxxG motif with the nanovesicles.
阿尔茨海默病是一种进行性严重神经退行性疾病，尽管全球都在做出巨大努力，但迄今为止仍无法治愈。我们设计了基于自组装肉豆蔻酰-KPGPK脂肽的生物相容性纳米囊泡，它可以抑制由Aβ蛋白的跨膜GxxxGxxxGxxxG基序和人髓鞘蛋白零形成的淀粉样蛋白原纤维，同时降低它们的神经毒性。各种光谱和显微镜研究表明，基于脂肽的纳米囊泡显著抑制Aβ和人髓鞘蛋白零蛋白前体从无规卷曲向β-折叠的转变，而这种转变是GxxxGxxxGxxxG基序介导的原纤维形成的前提条件。使用合成的Cy-3（FRET供体）和Cy-5（FRET受体）偶联的Aβ进行的荧光共振能量转移（FRET）分析也表明，纳米囊泡强烈抑制Aβ的原纤维形成。使用了小鼠神经母细胞瘤Neuro-2a细胞系，该细胞系显示出GxxxGxxxGxxxG介导的细胞毒性。然而，通过将GxxxGxxxGxxxG基序与纳米囊泡共同孵育，神经毒性已经降低。
