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A Novel Peptide For Delivery of Biomacromolecules Into Cells

A novel endosomal lytic peptide with a good balance of effective cargo delivery and not killing the cell in the process.

The cell plasma membrane is a greasy barrier that denies the entry of water-soluble macromolecules, like nucleic acids and proteins, into cells. To deliver drugs to cells that need them, different methods of delivery have been explored. Cationic peptides have been well-studied as vehicles for delivery but they can cause excessive membrane activity that would lead to cell death, making them undesirable for intracellular delivery purposes. There is a need to devise peptides with well-controlled membrane activities that do not cause direct damage to the cell membrane, however, this has been difficult to achieve.

In a recent study led by Professor Fei Hao from Suzhou Institute of Nano-tech and Nano-Bionics of the Chinese Academy of Sciences, the team had employed a strategy of hydrophobicity-tuning on a set of artificial peptides and discovered an optimised peptide that was particularly responsive to the acidic environment on the endosomal membrane.

It is known that well-conditioned cationic amphipathic peptides can match the properties of the target cell membrane to aid intracellular cargo delivery. These amphipathic peptides have both hydrophobic and hydrophilic ends, where the hydrophobic ends would aid the peptide in inserting into the membranes, and the hydrophilic ends would help the peptide remain soluble and later form helical shapes to break holes in the membranes. The cations present on the peptides also attract negatively charged acidic phospholipids and sialic acids that are often found in cell membranes but are highly enriched in endosomal membranes.

The present study focused on hydrophobicity, an important biophysical property that dictates the membrane activity of cationic amphipathic peptides. By fine-tuning hydrophobicity, Prof. Fei and colleagues balanced the two key actions of the peptide – being able to attach itself to the cell membrane without killing the cell and forming peptide assembled holes in the acidic endosomal membrane to allow cargo entry.

With the resultant peptide LP6, the team demonstrated its cytosolic delivery ability with membrane-impermeable protein, saporin. They incubated HeLa cells with saporin alone and observed little cell death, however, when incubated in the presence of LP6, cell death increased significantly. This suggests that LP6 could effectively promote cell cargo entry and aid the cytosolic delivery of biomacromolecules.

As approximately 75 per cent of the human proteome is intracellular and inaccessible to protein therapeutics, this study would be useful for the rational design and modification of more effective vehicle peptides for drug delivery of biomacromolecules into the cytosol. [APBN]

Source: Chen et al. (2021). Hydrophobicity-tuned anion responsiveness underlies endosomolytic cargo delivery mediated by amphipathic vehicle peptides. Journal of Biological Chemistry, 101364.