Cell penetrating peptides
The Foster critical distance of the conventional RET donor-recipient pair to penetrate the cell membrane into the cell is a prerequisite for many biological macromolecules to function within the cell, but the biological barrier effect of biofilms prevents many macromolecules from entering the cell, thus limiting the application of these substances in the therapeutic field to a large extent. Therefore, how to guide these substances to penetrate the cell membrane is an urgent problem to be solved. Currently, the main methods of mediating biomacromolecules to penetrate the cell membrane include cell penetrating peptides (CPPs), liposomes, adenoviruses, nanoparticles, shadow cells, etc. CPPs, on the other hand, are a class of peptides that directly cross the cell membrane into the cell in a non-receptor-dependent, non-classical endocytotic way. Their length is generally not more than 30 amino acids, and they are rich in basic amino acids. The amino acid sequence is usually positively charged.
Transmembrane mechanism
The transmembrane mechanism of a cell penetrating peptide (CPP) is different, and the specific mechanism of a cell penetrating peptide (CPP) depends on several parameters, such as molecular size (carrying substance), temperature, cell type, and stability in and out of the cell. The specific mechanism by which cell penetrating peptide (CPP) enters the cell is still unclear, and popular speculations include the following three:
A: inverted micelle model: CPPs enter the cytoplasm through the movement of phospholipid molecules on the cell membrane to form an inverted micelle structure.
B: Direct penetration, that is, pore formation model, CPPs forma transmembrane pore structure on the cell membrane and enter the cytoplasm.
C: Cellular uptake by endocytosis.
Cell penetrating peptide HIV TAT
Cell-penetrating peptides (such as HIV TAT) can enter cells in both direct penetration and endocytosis. HIV TAT or simply polyarginine can be designed as effective drug carriers, but how CPPS (such as HIV TAT) achieve membrane transport is still unclear. How does simple HIV TAT promote endocytosis mechanisms such as direct penetration and endocytosis? Researchers from Gerard Wong's lab investigated how HIV TAT interacts with the plasma membrane, cytoskeleton, and specific membrane receptors under different conditions to induce multiple transport pathways. Interestingly, TAT can have a variety of different reactions with the same sequence under different conditions, so the interaction with the cell membrane, cytoskeleton, and specific receptors can produce a variety of transport pathways. The transmembrane mechanism of CPP is very sensitive to the polypeptide sequence. If a hydrophobic residue is added to a pure hydrophilic CPP, its transport mechanism can be completely changed. For example, the simplest CPP prototype, polyspermidine (polyR), can induce the formation of a transmembrane pore structure on the cell membrane. Hydrophobic amino acids form positive curvature by insertion into the cell membrane, arginine can form both positive and negative curvature, lysine can only form negative curvature in one direction, which means that there is a compensation relationship between arginine and lysine/hydrophobic.If hydrophobicity contributes to the formation of negative Gaussian curvature, why is the hydrophobic content of TAT peptides relatively low? The reason is that CPPs use as few hydrophobic groups as possible to form a saddle-splay curvature. The difference in sequence is likely to induce only a brief pore-like transmembrane structure on the membrane, resulting in a shorter pore lifetime for CPP. Due to the different amino acid composition of CPP, TAT peptide can mediate endocytosis with or without receptors.
