Abstract
The hydrophilic nature of peptides and proteins renders them impermeable to cell membranes. Thus, in order to successfully deliver peptide and protein-based therapeutics across the plasma membrane or epithelial and endothelial barriers, a permeation enhancing strategy must be employed. Cell-penetrating peptides (CPPs) constitute a promising tool and have shown applications for peptide and protein delivery into cells as well as across various epithelia and the blood-brain barrier (BBB). CPP-mediated delivery of peptides and proteins may be pursued via covalent conjugation of the CPP to the cargo peptide or protein or via physical complexation obtained by simple bulk-mixing of the CPP with its cargo. Both approaches have their pros and cons, and which is the better choice likely relates to the physicochemical properties of the CPP and its cargo as well as the route of administration, the specific barrier and the target cell. Besides the physical barrier, a metabolic barrier must be taken into consideration when applying peptide-based delivery vectors, such as the CPPs, and stability-enhancing strategies are commonly employed to prolong the CPP half-life. The mechanisms by which CPPs translocate cell membranes are believed to involve both endocytosis and direct translocation, but are still widely investigated and discussed. The fact that multiple factors influence the mechanisms responsible for cellular CPP internalization and the lack of sensitive methods for detection of the CPP, and in some cases the cargo, further complicates the design and conduction of conclusive mechanistic studies.
Highlights
The increasing occurrence of life-threatening and serious debilitating diseases demands effective treatment with highly potent and acting molecules, such as therapeutic peptides and proteins, which comprise an increasing number of new drugs in the pipeline
The history of Cell-penetrating peptides (CPPs) goes back to 1988, where Frankel & Pabo discovered that the Human Immunodeficiency Virus (HIV) Trans-activator of transcription (Tat) protein possessed the ability to translocate across cellular membranes [1]
In addition to the efforts spent on the discovery of new CPPs, various strategies have been exploited to improve the efficiency of already known CPPs, either via improving their resilience to enzymatic degradation or by enhancing their membrane-penetrating propensity
Summary
The increasing occurrence of life-threatening and serious debilitating diseases demands effective treatment with highly potent and acting molecules, such as therapeutic peptides and proteins, which comprise an increasing number of new drugs in the pipeline. For therapeutic peptides and proteins having an intracellular target, a strategy that facilities permeation across the plasma membrane is essential for successful delivery to the target. In addition to the efforts spent on the discovery of new CPPs, various strategies have been exploited to improve the efficiency of already known CPPs, either via improving their resilience to enzymatic degradation or by enhancing their membrane-penetrating propensity These strategies include changing amino acid stereochemistry from L to D and the inclusion of β or γ-amino acids [3] as well as non-primary amino acids [4]. The CPPs have shown to be applicable for transepithelial [12] and transendothelial [13] delivery of therapeutic peptides and proteins In addition to their application as inert vectors for delivery of cargo molecules, an emerging concept is the dual-acting CPPs, which are both membrane permeating and bioactive. The choice of formulation approach, mechanism of membrane permeation, and limitations in the use of CPPs as delivery vectors will be discussed
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