Proteolytically Stable Diaza-Peptide Foldamers Mimic Helical Hot Spots of Protein–Protein Interactions and Act as Natural Chaperones,Journal of Medicinal Chemistry

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Proteolytically Stable Diaza-Peptide Foldamers Mimic Helical Hot Spots of Protein–Protein Interactions and Act as Natural Chaperones
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-08-26 , DOI: 10.1021/acs.jmedchem.3c00611
Chenghui Shi ₁ , Julia Kaffy ₁ , Tâp Ha-Duong ₁ , Jean-François Gallard ₂ , Alain Pruvost ₃ , Aloise Mabondzo ₃ , Lidia Ciccone ₄ , Sandrine Ongeri ₁ , Nicolo Tonali ₁

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A novel class of peptidomimetic foldamers based on diaza-peptide units are reported. Circular dichroism, attenuated total reflection –Fourier transform infrared, NMR, and molecular dynamics studies demonstrate that unlike the natural parent nonapeptide, the specific incorporation of one diaza-peptide unit at the N-terminus allows helical folding in water, which is further reinforced by the introduction of a second unit at the C-terminus. The ability of these foldamers to resist proteolysis, to mimic the small helical hot spot of transthyretin-amyloid β (Aβ) cross-interaction, and to decrease pathological Aβ aggregation demonstrates that the introduction of diaza-peptide units is a valid approach for designing mimics or inhibitors of protein–protein interaction and other therapeutic peptidomimetics. This study also reveals that small peptide foldamers can play the same role as physiological chaperone proteins and opens a new way to design inhibitors of amyloid protein aggregation, a hallmark of more than 20 serious human diseases such as Alzheimer’s disease.

中文翻译：

蛋白水解稳定的二氮杂肽折叠体模仿蛋白质-蛋白质相互作用的螺旋热点并充当天然伴侣

报道了一类基于二氮杂肽单元的新型肽模拟折叠体。圆二色性、衰减全反射 - 傅里叶变换红外、核磁共振和分子动力学研究表明，与天然母体九肽不同，在 N 末端特异性掺入一个二氮杂肽单元可以在水中进行螺旋折叠，这进一步得到了增强在C端引入第二个单元。这些折叠体能够抵抗蛋白水解、模拟运甲状腺素蛋白-淀粉样蛋白 β (Aβ) 交叉相互作用的小螺旋热点以及减少病理性 Aβ 聚集，这表明引入二氮杂肽单元是设计模拟物的有效方法或蛋白质-蛋白质相互作用抑制剂和其他治疗性肽模拟物。这项研究还揭示了小肽折叠体可以起到与生理伴侣蛋白相同的作用，并开辟了设计淀粉样蛋白聚集抑制剂的新方法，淀粉样蛋白聚集是阿尔茨海默氏病等 20 多种严重人类疾病的标志。

更新日期：2023-08-26

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