Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
J Chem Phys. 2019 Mar 7;150(9):095101. doi: 10.1063/1.5082194.
Peptides build from D-amino acids resist enzymatic degradation. The resulting extended time of biological activity makes them prime candidates for the development of pharmaceuticals. Of special interest are D-retro-inverso (DRI) peptides where a reversed sequence of D-amino acids leads to molecules with almost the same structure, stability, and bioactivity as the parent L-peptides but increased resistance to proteolytic degradation. Here, we study the effect of DRI-Aβ and DRI-Aβ peptides on fibril formation. Using molecular dynamics simulations, we compare the stability of typical amyloid fibril models with such where the L-peptides are replaced by DRI-Aβ and DRI-Aβ peptides. We then explore the likelihood for cross fibrilization of Aβ L- and DRI-peptides by investigating how the presence of DRI peptides alters the elongation and stability of L-Aβ-fibrils. Our data suggest that full-length DRI-peptides may enhance the fibril formation and decrease the ratio of soluble toxic Aβ oligomers, pointing out potential for D-amino-acid-based drug design targeting Alzheimer's disease.
由 D-氨基酸组成的肽可抵抗酶的降解。由此产生的生物活性延长时间使它们成为开发药物的首选。特别引人关注的是 D-反向（DRI）肽，其中 D-氨基酸的反向序列导致与母体 L-肽具有几乎相同结构、稳定性和生物活性的分子，但对蛋白水解降解的抗性增加。在这里，我们研究了 DRI-Aβ 和 DRI-Aβ 肽对纤维形成的影响。使用分子动力学模拟，我们比较了典型淀粉样纤维模型的稳定性，以及用 DRI-Aβ 和 DRI-Aβ 肽取代 L-肽的模型的稳定性。然后，我们通过研究 DRI 肽的存在如何改变 L-Aβ-纤维的伸长和稳定性，来探索 Aβ L-和 DRI-肽之间交叉纤维形成的可能性。我们的数据表明，全长 DRI-肽可能会增强纤维形成并降低可溶性有毒 Aβ 寡聚物的比例，这为针对阿尔茨海默病的基于 D-氨基酸的药物设计指出了潜力。
