1. Academic Validation
  2. Analysis of hydrophobic and hydrophilic moments of short penetrating peptides for enhancing mitochondrial localization: prediction and validation

Analysis of hydrophobic and hydrophilic moments of short penetrating peptides for enhancing mitochondrial localization: prediction and validation

  • FASEB J. 2019 Jul;33(7):7970-7984. doi: 10.1096/fj.201802748RR.
Marco Pirisinu 1 2 Pilar Blasco 1 2 Xueli Tian 1 3 Yang Sen 1 Ann M Bode 2 Kangdong Liu 1 3 4 5 Zigang Dong 1 2 3 4 5
Affiliations

Affiliations

  • 1 The China-U.S. (Henan) Hormel Cancer Institute, Zhengzhou, China.
  • 2 The Hormel Institute, University of Minnesota, Austin, Minnesota, USA.
  • 3 Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
  • 4 The Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, China.
  • 5 Collaborative Innovation Center, Cancer Chemoprevention of Henan, Zhengzhou, China.
Abstract

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.

Keywords

cell-penetrating peptides; drug delivery; molecular dynamics; specificity.

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