Cell-penetrating Peptides (CPPs) Used in Drug Delivery Systems

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The cell membrane is a natural barrier composed of a lipid bilayer, which restricts the entry of external substances into the cell and ensures the stability of the intracellular environment. At the same time, to maintain a stable internal environment, the human body possesses various physiological barriers, such as the blood-brain barrier (BBB), blood-retinal barrier, and placental barrier. One of the main obstacles to drug delivery is the inability of drugs to penetrate the cell membrane and physiological barriers, thereby preventing them from exerting their therapeutic effects inside the cell.

Cell-penetrating peptides (CPPs) are short peptides capable of entering cells without disrupting membrane integrity. They typically consist of 5 to 30 amino acids and are rich in basic amino acids, including arginine and lysine. Under physiological conditions, CPPs share two common characteristics: a positive charge and amphiphilicity. In recent years, CPPs have been widely applied in drug delivery systems.

The recognized mechanisms by which CPPs penetrate cell membranes fall into two categories: endocytosis and direct translocation. Endocytosis is an energy-dependent process and includes three main pathways: macropinocytosis, caveolae-mediated endocytosis (CvME), and clathrin-mediated endocytosis (CME). In contrast, direct translocation is an energy-independent process facilitated by electrostatic interactions between the positively charged CPPs and the negatively charged membrane components and phospholipid bilayer, promoting direct membrane permeation. Several models have been proposed for direct penetration, including the barrel-stave model, carpet model, toroidal pore model, and inverted micelle model.

A summary of the cell-penetrating peptide used in drug delivery is as follows:

1. Polyarginine

Single-letter code: H2N-RRRRRRRRR-OH

Three-letter code: H2N-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-OH

Number of amino acids: 9

Molecular formula: C54H110N36O10

Average molecular weight (MW): 1423.69

2. Transportan 10 (TP10)

Single-letter code: H2N-AGYLLGKINLKALAALAKKIL-OH

Three-letter code: H2N-Ala-Gly-Tyr-Leu-Leu-Gly-Lys-Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-OH

Number of amino acids: 21

Molecular formula: C104H184N26O24

Average molecular weight (MW): 2182.73

3. Tumor-Lineage Homing CPP

Single-letter code: H2N-RLYMRYYSPTTRRYG-OH

Three-letter code: H2N-Arg-Leu-Tyr-Met-Arg-Tyr-Tyr-Ser-Pro-Thr-Thr-Arg-Arg-Tyr-Gly-OH

Number of amino acids: 15

Molecular formula: C89H135N27O23S1

Average molecular weight (MW): 1983.26

4. dNP2

Single-letter code: H2N-CKIKKVKKKGRKKIKKVKKKGRK-OH

Three-letter code: H2N-Cys-Lys-Ile-Lys-Lys-Val-Lys-Lys-Lys-Gly-Arg-Lys-Lys-Ile-Lys-Lys-Val-Lys-Lys-Lys-Gly-Arg-Lys-OH

Number of amino acids: 23

Molecular formula: C125H245N43O24S1

Average molecular weight (MW): 2766.62

5. RVRR

Single-letter code: H2N-RVRR-OH

Three-letter code: H2N-Arg-Val-Arg-Arg-OH

Number of amino acids: 4

Molecular formula: C23H47N13O5

Average molecular weight (MW): 585.70

6. L-penetratin

Single-letter code: H2N-RQIKIWFQNRRMKWKK-OH

Three-letter code: H2N-Arg-Gln-Ile-Lys-Ile-Trp-Phe-Gln-Asn-Arg-Arg-Met-Lys-Trp-Lys-Lys-OH

Number of amino acids: 16

Molecular formula: C104H168N34O20S1

Average molecular weight (MW): 2246.73

7. Activable CPP (ACPP)

Single-letter code: H2N-CRRRRRRRRGGGPKKKKKK-OH

Three-letter code: H2N-Cys-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Gly-Gly-Gly-Pro-Lys-Lys-Lys-Lys-Lys-Lys-OH

Number of amino acids: 19

Molecular formula: C98H191N49O20S1

Average molecular weight (MW): 2407.95

8. LH2

Single-letter code: Ac-LHHLCHLLHHLCHLAG-CONH2

Three-letter code: Ac-Leu-His-His-Leu-Cys-His-Leu-Leu-His-His-Leu-Cys-His-Leu-Ala-Gly-CONH2

Number of amino acids: 16

Molecular formula: C85H131O17N29S2

Average molecular weight (MW): 1895.26

9. Cancer Cell Line Specific CPP

Single-letter code: H2N-RLYMRYYSPTTRRYG-OH

Three-letter code: H2N-Arg-Leu-Tyr-Met-Arg-Tyr-Tyr-Ser-Pro-Thr-Thr-Arg-Arg-Tyr-Gly-OH

Number of amino acids: 15

Molecular formula: C89H135N27O23S1

Average molecular weight (MW): 1983.26

10. T2

Single-letter code: H2N-FKKFFRKLL-OH

Three-letter code: H2N-Phe-Lys-Lys-Phe-Phe-Arg-Lys-Leu-Leu-OH

Number of amino acids: 9

Molecular formula: C63H99N15O10

Average molecular weight (MW): 1226.55

Cell-penetrating Peptides (CPPs) at Creative Peptides

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