Peptide Knowledge Center
Research on CPPs
What are CPPs?
Green et al. first discovered the small molecule polypeptide TAT with the ability to penetrate the membrane in 1988, and then researchers discovered many short amino acid sequences with the function of penetrating the cell membrane and named them CPPs. About 1 700 CPPs have been reported so far, which can be classified according to their sources, physicochemical properties or biomedical applications.
CPPs and their classification CPPs are small molecule polypeptides that can be combined with macromolecules through covalent bonds (such as disulfide bonds, etc.), non-covalent bonds (such as electrostatic interactions, etc.) or modified macromolecules to other carriers (such as liposomes, etc.) carry macromolecules across cell membranes. CPPs are non-immunogenic molecules, usually not antigenic and cytotoxic, stable under physiological conditions, and the substances they carry include proteins (such as antibodies, etc.), nucleic acids (such as siRNA, DNA, RNA, etc.), imaging agents (such as fluorescence group, MRI contrast agent, etc.) and small molecule therapeutic drugs (such as cantharidin, etc.). In addition, some CPPs themselves have biological effects, such as the penetrating peptide buforin II b, which itself has tumor suppressor properties.
According to different sources, CPPs can be divided into 3 categories: 1) Protein-derived peptides, which are derived from short fragments on natural protein domains, have no cell specificity, and have the same transport efficiency at different temperatures (4-37 °C), such as VP22, gH625, etc.; 2) Model peptides, obtained by transforming natural CPPs, and designed to simulate the membrane-penetrating properties of known CPPs, such as the amphiphilic cell-penetrating peptide MPG; 3) Synthetic peptides, combining different sources of Chimeric peptides produced by conjugation of hydrophilic or hydrophobic domains, such as Pep-1 is an amphiphilic peptide containing 3 domains, a hydrophobic tryptophan-rich region and a hydrophilic lysine-rich region regions and connecting regions for enhanced stability.
CPPs are classified into cationic, amphiphilic, and hydrophobic based on their physicochemical properties. Among them, cationic CPPs have the most content and are mainly composed of positively charged amino acids, such as arginine, lysine and histidine, of which arginine is the most important component, such as polyarginine penetrating peptide R8, R9 et al. Amphiphilic CPPs consist of a hydrophobic N-terminus, a charged domain, and a hydrophilic C-terminus, and are amphipathic at pH 7.0 because their primary sequence contains polar and non-polar amino acids, such as MPG , Pep-l and so on. Hydrophobic CPPs consist of a positively charged N-terminus, a hydrophobic H domain, and a negatively charged C-terminus, have high affinity for the hydrophobic domain of the cell membrane, and are able to cross the cell membrane in an energy-dependent manner, such as Pep-7.
According to whether CPPs have tumor targeting, they are divided into tumor-specific and non-tumor-specific CPPs. Tumor-specific CPPs are designed based on substances that are highly expressed or specifically expressed on the surface of tumor cells, such as cyclic RGD peptides that express high integrins on the surface of tumor cells and activatable cell-penetrating peptides that express high matrix metalloproteinases on the surface of tumor cells.