Membrane Internalization Mechanisms and Design Strategies of Arginine-Rich Cell-Penetrating Peptides

Abstract

Cell-penetrating peptides (CPPs) have been discovered to deliver chemical drugs, nucleic acids, and macromolecules to permeate cell membranes, creating a novel route for exogenous substances to enter cells. Up until now, various sequence structures and fundamental action mechanisms of CPPs have been established. Among them, arginine-rich peptides with unique cell penetration properties have attracted substantial scientific attention. Due to the positively charged essential amino acids of the arginine-rich peptides, they can interact with negatively charged drug molecules and cell membranes through non-covalent interaction, including electrostatic interactions. Significantly, the sequence design and the penetrating mechanisms are critical. In this brief synopsis, we summarize the transmembrane processes and mechanisms of arginine-rich peptides; and outline the relationship between the function of arginine-rich peptides and the number of arginine residues, arginine optical isomers, primary sequence, secondary and ternary structures, etc. Taking advantage of the penetration ability, biomedical applications of arginine-rich peptides have been refreshed, including drug/RNA delivery systems, biosensors, and blood-brain barrier (BBB) penetration. Understanding the membrane internalization mechanisms and design strategies of CPPs will expand their potential applications in clinical trials.

Arginine Homopeptide of 11 Residues as a Model of Cell-Penetrating Peptides in the Interaction with Bacterial Membranes

“…Arg-rich peptides have been studied as cell-penetrating peptides and used as vehicles to internalize other molecules in eukaryotic cells and as antibacterial peptides with targets within the cell [27,28]. In this context, the interaction with the membrane has been the subject of various studies, due to its internalization capacity without causing membrane disruption.…”

“…It is well demonstrated that Arg-rich membrane-penetrating peptides enter the cell through a mechanism mediated by interaction with the negative groups of membrane lipids. In this mechanism, the exchange of counterions promotes the formation of amphiphilic lipid-amino acid complexes, helping the cell internalization process [27][28][29][30]. In this context, some amino acids seem to favor interaction with the membrane, as is the case of Trp, which has been reported to enhance the interaction of Arg-rich CPPs with membranes due to π-ion pair interactions, also depending on the number of Trp residues present in the sequence, and has been used as a modifier in Arg-rich peptides to increase their internalization capacity [30,31].…”

Peptide-Drug Conjugates: A New Hope for Cancer Management

“…Cell-penetrating peptides are arginine-rich peptides, and due to their positive charge, they interact with negatively charged drug molecules and cell membranes through non-covalent interaction, including electrostatic interactions. As such, the application of these arginine-rich peptides has been used to deliver biosensors, drugs, and vaccines and allows entry through the blood-brain barrier [ 219 ]. An example is the use of these peptides linked to chemotherapeutic drugs, such as doxorubicin, for its specific delivery to triple-negative breast cancers [ 220 ].…”

A cationic lipid with advanced membrane fusion performance for pDNA and mRNA delivery

“…The guanidine of arginine could form bidentate hydrogen bonds with the negative phosphates, sulfates, and carboxylates on the cell surface and be driven into cells. 11 Our groups also did some explorations in screening the types and structures of amino acids and found that the structure, stability, size, and construction of assemblies also significantly affected the transfection efficiency of lipoplexes, especially in the presence of serum. As well, the hydrophobic tail of lipids mainly affects the assembly, which has been widely studied with a focus on the length ( C ), unsaturation ( Ω ), and the number of alkyl chains ( N ).…”