Taming Cell Penetrating Peptides: Never Too Old To Teach Old Dogs New Tricks

Abstract

Cell penetrating peptides (CPPs) have received substantial attention due to their intrinsic property to cross plasma membranes or even as helpers to facilitate the cellular entry of drug molecules, macromolecules, and nanoparticles. Although CPPs and CPP-like peptides provided versatile platforms for drug delivery, their nonselectivity or lack of delivery efficiency is stirring up debates as to the tactics for the optimizing the CPPs themselves. The good news is that, as spurred by the recent progress in the understanding of tumor microenvironment as well as biochemistry and material sciences, we have made attempts in working on perfecting or even "taming" CPPs and CPP-functionalized drug vectors for tumor delivery, and some of them afforded gratifying results. Due to the fact that these peptides are mainly short peptides made up of amino acids (5-30 amino acids), the addition, modification, or replacement of amino acids might lead to surprisingly improved performance. Several novel environment-responsive CPPs or CPP-like peptides have also been discovered. In this review we will discuss the measures taken to harness the power of CPPs and the discovery of environment-responsive peptides with CPP properties.

Conformationally constrained peptides for drug delivery

“…14,15 To design peptides with tailored functions, it is vital to confine the peptide backbone architecture to a defined conformation; else, we have to wait for random hits with very minimal possibility of an informed and structured design paradigm getting established. 16 A stable template structure offers the possibility of optimizing design parameters like amphipathicity, topology, overall size, and sequence length.…”

Stimuli-Sensitive Cell Penetrating Peptide-Modified Nanocarriers

“…Conjugation of CPPs to increase cellular uptake stems from mimicry of viruses uptake. Indeed, among the most powerful CPPs are the transcription and transactivator from HIV-1 (TAT) and VP22 of herpes virus, both promoters of virus transduction [10,11].…”

“…CPPs are either natural or synthetic and possess cationic, amphiphatic or hydrophobic membrane translocation domains that enhanced the intracellular delivery of several types of nanocarriers [7,[11][12][13]. However, conjugation of CPPs is a double-edged sword as their membrane translocation power is limited by the lack of CPP tropism to diseased tissues, with detrimental uptake of CPP-modified nanocarriers by normal tissues [11,14].…”

“…Exposition of CPP only after activation by pathophysiological traits has been proposed to reduce the internalization of CPP-modified nanocarriers by normal tissues [11,14]. In such environment-responsive CPP-modified nanocarriers, the CPP is hold in a stimuli-labile scabbard until being drawn out after encountering the appropriate stimuli.…”

“…In such environment-responsive CPP-modified nanocarriers, the CPP is hold in a stimuli-labile scabbard until being drawn out after encountering the appropriate stimuli. The principal environment stimuli used are light, acidosis, redox imbalance and proteases [11,15].…”