Bio-Membrane Internalization Mechanisms of Arginine-Rich Cell-Penetrating Peptides in Various Species.

Han-Jung Lee,Shiow-Her Chiou,Betty Revon Liu,Yue-Wern Huang

doi:10.3390/membranes12010088

Abstract

Recently, membrane-active peptides or proteins that include antimicrobial peptides (AMPs), cytolytic proteins, and cell-penetrating peptides (CPPs) have attracted attention due to their potential applications in the biomedical field. Among them, CPPs have been regarded as a potent drug/molecules delivery system. Various cargoes, such as DNAs, RNAs, bioactive proteins/peptides, nanoparticles and drugs, can be carried by CPPs and delivered into cells in either covalent or noncovalent manners. Here, we focused on four arginine-rich CPPs and reviewed the mechanisms that these CPPs used for intracellular uptake across cellular plasma membranes. The varying transduction efficiencies of them alone or with cargoes were discussed, and the membrane permeability was also expounded for CPP/cargoes delivery in various species. Direct membrane translocation (penetration) and endocytosis are two principal mechanisms for arginine-rich CPPs mediated cargo delivery. Furthermore, the amino acid sequence is the primary key factor that determines the cellular internalization mechanism. Importantly, the non-cytotoxic nature and the wide applicability make CPPs a trending tool for cellular delivery.

Highlights

The plasma membrane is a natural barrier that separates intracellular components from the external environment and keeps the balance of osmotic pressure
We focus on cell-penetrating peptides (CPPs), which are highly applied in biomedical therapeutics and regarded as a potent drug delivery system [6]
Endocytosis and direct membrane translocation have been proposed as the two major mechanisms used for CPP internalization

Summary

Introduction

The plasma membrane is a natural barrier that separates intracellular components from the external environment and keeps the balance of osmotic pressure. The first CPP, a short peptide containing 11 cationic residues, is referred to as the protein transduction domain (PTD). According to the peptide nature, CPPs were categorized into three major groups: protein derived, synthetic, and chimeric peptides [11]. According to their chemical and physical properties, most studies have classified CPPs into cationic, amphipathic, and hydrophobic groups [6]. Most CPPs contain less than 30 amino acids, but the shortest CPP is a peptide consisting of five residues (L5a, see Appendix A, Table A1) [13,14] These CPPs can enter cells by themselves but can take cargoes with them to cross cell membranes. Various modifications of the primary sequences of CPPs, types of cargoes for delivery, combination manners of cargoes, and even concentrations of CPPs were important factors in contributing to alternative entry routes into cells [27,30,31,34,38,40]

Mechanisms of Cellular Internalization

Evidence of Cellular Internalization

Conclusions