The China-U.S. (Henan) Hormel Cancer Institute, Zhengzhou, China.
The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
FASEB J. 2019 Jul;33(7):7970-7984. doi: 10.1096/fj.201802748RR. Epub 2019 Mar 27.
Pharmaceutical interest in targeting mitochondria is increasing because of their contribution in incurable diseases. However, the inner mitochondrial layer represents a major hurdle to overcome for most drugs. Penetrating peptides are a promising strategy for drug delivery, but the absence of standard principles and reliable prediction tools limits the design and discovery of sequences with improved organelle specificity. In our hypothesis, peptide local flexibility represents a valuable source to predict peptide performance. Here, a pool of short nonnatural peptides was designed with the same amino acid content but different positioning. Molecular dynamics and membrane-transfer simulations were used to generate the low-energy conformers in extra, intracellular, and membrane-inserted environments. The contributions of the hydrophobic and hydrophilic side chain-exposed surfaces revealed that the amino acid's relative position significantly affected the simulated peptide's dynamics. Based on the structural versatility, we predicted the peptides' behavior and the sequence with the most efficient membrane penetration and mitochondrial localization. The prediction and the improved performance of our peptides were experimentally confirmed and compared with a reported mitochondrial-targeting sequence. We demonstrated that an accurate understanding of the structural versatility is a valid aid for future works in designing sequences with improved mitochondrial targeting.-Pirisinu, M., Blasco, P., Tian, X., Sen, Y., Bode, A. M., Liu, K., Dong, Z. Analysis of hydrophobic and hydrophilic moments of short penetrating peptides for enhancing mitochondrial localization: prediction and validation.
由于线粒体在不治之症中的作用，制药行业对其靶向治疗的兴趣日益增加。然而，对于大多数药物来说，线粒体的内层是一个主要的障碍。穿透肽是一种很有前途的药物传递策略，但缺乏标准原则和可靠的预测工具，限制了具有改善细胞器特异性的序列的设计和发现。在我们的假设中，肽的局部灵活性代表了预测肽性能的有价值的来源。在这里，设计了一组具有相同氨基酸含量但不同位置的短非天然肽。分子动力学和膜转移模拟用于在细胞外、细胞内和膜插入环境中生成低能量构象。疏水性和亲水性侧链暴露表面的贡献表明，氨基酸的相对位置显著影响模拟肽的动力学。基于结构的多功能性，我们预测了肽的行为以及具有最高效率的膜穿透和线粒体定位的序列。我们的预测和肽的改进性能通过实验得到了证实，并与报道的靶向线粒体的序列进行了比较。我们证明了对结构多功能性的准确理解是设计具有改进的线粒体靶向性的序列的有效辅助手段。
