Cell-Penetrating Peptides Using Cyclic α,α-Disubstituted α-Amino Acids with Basic Functional Groups

Cell-penetrating peptides (CPPs) comprise efficient peptide-based delivery vectors. Owing to the inherent poor enzymatic stability of peptides, CPPs displaying partial or full replacement of l-amino acids with the corresponding d-amino acids might possess advantages as delivery vectors. Thus, the present study aims to elucidate the membrane- and metabolism-associated effects of l-Penetratin (l-PEN) and its corresponding all-d analog (d-PEN). These effects were investigated when exerted on hepatocellular (HepG2) or intestinal (Caco-2 and IEC-6) cell culture models. The head-to-head comparison of these enantiomeric CPPs included evaluation of their effects on cell viability and morphology, epithelial membrane integrity, and cellular ultrastructure. In all investigated cell models, a rapid decrease in cell viability, pronounced membrane perturbation and an altered ultrastructure were detected upon exposure to d-PEN. At equimolar concentrations, these observations were less pronounced or even absent for cells exposed to l-PEN. Both CPPs remained stable for at least 2 h during exposure to proliferating cells (cultured for 24 h), although d-PEN exhibited a longer half-life when compared with that of l-PEN when exposed to well-differentiated cell monolayers (cultured for 18–20 days). Thus, the stereochemistry of the CPP penetratin significantly influences its effects on cell viability and epithelial integrity when profiled against a panel of mammalian cells.

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Plasmid DNA delivery by arginine-rich cell-penetrating peptides containing unnatural amino acids

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2016.04.031 ◽

2016 ◽

Vol 24 (12) ◽

pp. 2681-2687 ◽

Cited By ~ 28

Author(s):

Takuma Kato ◽

Hiroko Yamashita ◽

Takashi Misawa ◽

Koyo Nishida ◽

Masaaki Kurihara ◽

...

Keyword(s):

Amino Acids ◽

Plasmid Dna ◽

Unnatural Amino Acids ◽

Dna Delivery ◽

Cell Penetrating Peptides ◽

Cell Penetrating

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Oligoalanine helical callipers for cell penetration

Chemical Communications ◽

10.1039/c8cc02304b ◽

2018 ◽

Vol 54 (50) ◽

pp. 6919-6922 ◽

Cited By ~ 6

Author(s):

Marta Pazo ◽

Marisa Juanes ◽

Irene Lostalé-Seijo ◽

Javier Montenegro

Keyword(s):

Amino Acids ◽

Rational Design ◽

Chemical Space ◽

Cell Penetrating Peptides ◽

Short Peptides ◽

Cell Penetration ◽

Basic Amino Acids ◽

Cell Penetrating ◽

Natural Amino Acids

Even for short peptides that are enriched in basic amino acids, the large chemical space that can be spanned by combinations of natural amino acids hinders the rational design of cell penetrating peptides.

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Delivery of SiC-based nanoparticles into live cells driven by cell-penetrating peptides SAP and SAP-E

RSC Advances ◽

10.1039/c4ra10688a ◽

2015 ◽

Vol 5 (26) ◽

pp. 20498-20502 ◽

Cited By ~ 4

Author(s):

T. Serdiuk ◽

I. Bakanovich ◽

V. Lysenko ◽

S. A. Alekseev ◽

V. A. Skryshevsky ◽

...

Keyword(s):

Functional Groups ◽

Cell Penetrating Peptides ◽

Live Cells ◽

Nanoparticle Delivery ◽

Cell Penetrating ◽

Covalent Conjugates

Cell-penetrating peptides enhance nanoparticle delivery into cells most efficiently if surface and peptide functional groups “match” to form non-covalent conjugates.

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Molecular dynamics study of the internalization of cell-penetrating peptides containing unnatural amino acids across membranes

Nanoscale Advances ◽

10.1039/d1na00674f ◽

2021 ◽

Author(s):

Joan Gimenez-Dejoz ◽

Keiji Numata

Keyword(s):

Molecular Dynamics ◽

Amino Acids ◽

Unnatural Amino Acids ◽

Biological Membranes ◽

Cell Penetrating Peptides ◽

Delivery Systems ◽

Cell Penetrating ◽

Target Molecules

Peptide-based delivery systems that deliver target molecules into cells have been gaining traction. These systems need cell-penetrating peptides (CPPs), which have the remarkable ability to penetrate into biological membranes and...

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Enhanced drug toxicity by conjugation of platinum drugs to polymers with guanidine containing zwitterionic functional groups that mimic cell-penetrating peptides

Polymer Chemistry ◽

10.1039/c4py00802b ◽

2014 ◽

Vol 5 (22) ◽

pp. 6600-6610 ◽

Cited By ~ 10

Author(s):

Khairil Juhanni Abd Karim ◽

Robert H. Utama ◽

Hongxu Lu ◽

Martina H. Stenzel

Keyword(s):

Functional Groups ◽

Drug Toxicity ◽

Cell Penetrating Peptides ◽

Platinum Drugs ◽

Cell Penetrating ◽

Solubility Enhancers ◽

Groove Binders

Inspired by the Ringsdorf model, statistical copolymers with solubility enhancers, platinum drugs and groove binders were compared.

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Amphiphilic Cell-Penetrating Peptides Containing Natural and Unnatural Amino Acids as Drug Delivery Tools and Antimicrobial Agents

10.36837/chapman.000221 ◽

2021 ◽

Author(s):

◽

David Salehi

Keyword(s):

Drug Delivery ◽

Amino Acids ◽

Unnatural Amino Acids ◽

Antimicrobial Agents ◽

Cell Penetrating Peptides ◽

Cell Penetrating

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Peptides – Molecular Allrounders

CHIMIA International Journal for Chemistry ◽

10.2533/chimia.2021.525 ◽

2021 ◽

Vol 75 (6) ◽

pp. 525-529

Author(s):

Helma Wennemers

Keyword(s):

Amino Acids ◽

Supramolecular Chemistry ◽

Asymmetric Catalysis ◽

Functional Diversity ◽

Chemical Biology ◽

Cell Penetrating Peptides ◽

Peptide Catalysts ◽

Collagen Peptides ◽

Cell Penetrating

The enormous structural and functional diversity available through combining different amino acids into peptides offers numerous exciting opportunities. This article summarizes recent research highlights from my laboratory in the areas of asymmetric catalysis, supramolecular chemistry, and chemical biology. This scope includes the development of bioinspired peptide catalysts, synthetic collagen peptides, supramolecular porous assemblies, and cell-penetrating peptides.

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Cell-Penetrating Peptides: Emerging Tools for mRNA Delivery

Pharmaceutics ◽

10.3390/pharmaceutics14010078 ◽

2021 ◽

Vol 14 (1) ◽

pp. 78

Author(s):

Hidetomo Yokoo ◽

Makoto Oba ◽

Satoshi Uchida

Keyword(s):

Amino Acids ◽

Genetic Diseases ◽

Cell Penetrating Peptides ◽

Delivery Systems ◽

Endosomal Escape ◽

Messenger Rnas ◽

Distinctive Features ◽

Cell Penetrating ◽

Preventive Vaccination ◽

Natural Amino Acids

Messenger RNAs (mRNAs) were previously shown to have great potential for preventive vaccination against infectious diseases and therapeutic applications in the treatment of cancers and genetic diseases. Delivery systems for mRNAs, including lipid- and polymer-based carriers, are being developed for improving mRNA bioavailability. Among these systems, cell-penetrating peptides (CPPs) of 4–40 amino acids have emerged as powerful tools for mRNA delivery, which were originally developed to deliver membrane-impermeable drugs, peptides, proteins, and nucleic acids to cells and tissues. Various functionalities can be integrated into CPPs by tuning the composition and sequence of natural and non-natural amino acids for mRNA delivery. With the employment of CPPs, improved endosomal escape efficiencies, selective targeting of dendritic cells (DCs), modulation of endosomal pathways for efficient antigen presentation by DCs, and effective mRNA delivery to the lungs by dry powder inhalation have been reported; additionally, they have been found to prolong protein expression by intracellular stabilization of mRNA. This review highlights the distinctive features of CPP-based mRNA delivery systems.

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