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Peptidomimetics That Inhibit and Partially Reverse the Aggregation of Aβ1–42
Biochemistry ( IF 2.9 ) Pub Date : 2017-08-25 00:00:00 , DOI: 10.1021/acs.biochem.7b00223
Tina Stark , Tobias Lieblein , Maximilian Pohland , Elisabeth Kalden , Petra Freund , René Zangl , Rekha Grewal 1 , Mike Heilemann , Gunter P. Eckert , Nina Morgner , Michael W. Göbel
Affiliation  

The peptide sequence KLVFF resembles the hydrophobic core of the Aβ peptide known to form amyloid plaques in Alzheimer’s disease. Starting from its retro-inverso peptide, we have synthesized three generations of peptidomimetics. Step by step natural amino acids have been replaced by aromatic building blocks accessible from the Pd-catalyzed Catellani reaction. The final compound 18 is stable against proteolytic decay and largely prevents the aggregation of Aβ1–42 over extended periods of time. The activity of the new inhibitors was tested first by fluorescence correlation spectroscopy. For closer examination of compound 18, additional techniques were also applied: laser-induced liquid bead ion desorption mass spectrometry, confocal laser scanning microscopy, thioflavin T fluorescence, and gel electrophoresis. Compound 18 not only retards the aggregation of chemically synthesized Aβ but also can partially dissolve the oligomeric structures. Thioflavin binding mature fibrils, however, seem to resist the inhibitor.

中文翻译:

抑制和部分逆转Aβ1–42聚集的拟肽

肽序列KLVFF类似于已知在阿尔茨海默氏病中形成淀粉样斑块的Aβ肽的疏水核心。从逆反肽开始,我们合成了三代拟肽。逐步将天然氨基酸替换为可从Pd催化的Catellani反应中获得的芳香族结构单元。最终化合物18对蛋白水解衰变是稳定的,并在较长的时间内很大程度上防止了Aβ1–42的聚集。首先通过荧光相关光谱法测试了新抑制剂的活性。用于化合物18的仔细检查,还应用了其他技术:激光诱导的液珠离子解吸质谱,共聚焦激光扫描显微镜,硫代黄素T荧光和凝胶电泳。化合物18不仅阻碍化学合成的Aβ的聚集,而且可以部分溶解寡聚结构。然而,硫黄素结合的成熟原纤维似乎抵抗该抑制剂。
更新日期:2017-08-25
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