Cell-Penetrating Peptides Synthesis (CPPs)


Peptide, protein and gene biomacromolecule drugs play an important role in the treatment of many diseases, but due to their large size and low lipophilic properties, they can not effectively pass through the cell membrane, which limits the application of these biomacromolecules in the biomedical field.


Cell penetrating peptides (CPPs) are a kind of small molecular peptides with strong transmembrane transport ability, which can carry many kinds of macromolecular substances such as peptides, proteins and nucleic acids into cells, opening up a new way for exogenous substances to enter cells. As a new delivery tool, cell penetrating peptides has a broad application prospect.

1) Cationic CPPs:It is composed of short peptides rich in Arginine, Lysine and Histidine.The minimum amount of arginine is 8 for penetration.

2) Amphiphilic CPPs: It is composed of hydrophobic peptide sequence covalently linked with NLSs (nuclear localization sequences).

3) α-helix amphiphilic CPPs:The hydrophilic and hydrophobic amino acid residues are located on different surfaces of the helix structure by combining the α-helix with the membrane.

4) β-sheet amphiphilic CPPs:The ability to form β-sheet is very important for its membrane penetrating ability. 

5) Proline enriched CPPs: it is easy to form poly-proline II (PPII) in pure water when proline is  rich in peptide structure. 

6) CPPs from natural existence:It refers to the peptide region of natural protein, which mainly transports protein to intracellular.

 Sequences and origins of cell penetrating peptides( CPPs) mentioned above

Cell penetrating peptidesSequenceOrigin
TATYGRKKRRQRRRTranscription factor coded by the HIV
PenetratinRQIKIWFQNRRMKWKD. melanogaster transcription factor
pVECLLIILRRRIRKQAHAHSMurine vascular endothelial-cadherin protein
AntitrypsiCSIPP EVKFN KPFVYLISynthesic
TransportanGWTLNSAGYLLGKINLKALAALAKKILMinimal active part of galanin
Tat (48-60)GRKKRRQRRRPPQHIV-1 protein
(Arg) 7RRRRRRRSynthesic

Application of Cell Penetrating Peptides

CPPs based drug delivery system has been used in the treatment of various diseases, including nervous diseases, asthma, ischemia, diabetes and cancer, among which cancer treatment is the first.


√ Combine small molecule anticancer drugs with CPPs to mediate these small molecule drugs into cancer cells.

Dubikovskaya et al. connected the Arg8 (RR-8) with the anticancer drug paclitaxel by disulfide bond to form covalent compound of Arg8 with paclitaxel . The results showed that covalent compound was more likely to induce apoptosis than paclitaxel alone.


√ The function of these proteins can be restored by transferring the corresponding proteins or peptide of tumor suppressor genes to cancer cells, so as to achieve the purpose of cancer treatment.


√ Combining siRNA (small interference RNA) with CPPs in the form of covalent / noncovalent, can help it pass through the cell membrane and play an anti-cancer role.


√ Mediates the transmembrane transport of various nanoparticles, such as magnetic nanoparticles, lipid nanoparticles, gold nanoparticles, micelles and quantum dots, to form various complexes and improve the efficiency of membrane penetration.


At present, the research on CPPs delivery system is more and more in-depth, and cell membrane penetrating peptide mediated transduction technology provides a new way for exogenous biological molecules to enter cells. And we will also have ability to synthesize more powerful and  less or no cytotoxic CPPs for disease treatment and other aspects.


1.Hansen M,Kilk K,Langel U,et al.Predicting cell penetrating peptides[J].Adv Drug Deliv Rev,2008,60(4-5):572-579

2.Juliano R.Review of cell penetrating peptides:processes and applications[J].J Control Release,2003,93(1):88-89

3.Nakase I,Takeuchi T,Tanaka G,et al.Methodogical and cellular aspects that govern the internalization mechanisms of arginine-rich cell penetrating peptides[J].Adv drug delive rev.2018.60(4-5):598-607