Translocation of cell-penetrating peptides across the plasma membrane is controlled by cholesterol and microenvironment created by membranous proteins

Pae, Janely; Säälik, Pille; Liivamägi, Laura; Lubenets, Dmitri; Arukuusk, Piret; Langel, Ülo; Pooga, Margus

doi:10.1016/j.jconrel.2014.07.002

Cited by 65 publications

(74 citation statements)

References 52 publications

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“…Using such vesicles, it has been shown that there is a direct correlation between the cellular uptake of penetratin (and some analogs) and its binding to plasma membrane derived vesicles. Other experiments have shown that multiple CPPs, including tat , penetratin, transportan and transportan 10 can accumulate inside plasma membrane derived vesicles[73,74], although the degree of membrane disruption is unknown. Vesicle surface interactions are dynamic and driven by multiple cell surface moieties[75].…”

Section: Translocation Across Membranesmentioning

confidence: 99%

See 1 more Smart Citation

Mechanism Matters: A Taxonomy of Cell Penetrating Peptides

Kauffman

Fuselier

et al. 2015

Trends in Biochemical Sciences

293

322

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The permeability barrier imposed by cellular membranes limits the access of exogenous compounds to the interior of cells. Researchers and patients alike would benefit from efficient methods for intracellular delivery of a wide range of membrane-impermeant molecules, including biochemically active small molecules, imaging agents, peptides, peptide nucleic acids, proteins, RNA, DNA, and nanoparticles. There has been a sustained effort to exploit cell penetrating peptides (CPPs) for the delivery of such useful cargoes in vitro and in vivo because of their biocompatibility, ease of synthesis, and controllable physical chemistry. Here, we discuss the many mechanisms by which CPPs can function, and describe a taxonomy of mechanisms that could be help organize future efforts in the field.

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Section: Translocation Across Membranesmentioning

confidence: 99%

“…Vesicle surface interactions are dynamic and driven by multiple cell surface moieties[75]. The translocation of CPPs across such native membranes favors liquid disordered membrane domains low in cholesterol and sphingomyelin[73,74]. …”

Section: Translocation Across Membranesmentioning

confidence: 99%

Mechanism Matters: A Taxonomy of Cell Penetrating Peptides

Kauffman

Fuselier

et al. 2015

Trends in Biochemical Sciences

293

322

View full text Add to dashboard Cite

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“…24 Cooling cells to 4 °C provides another challenge in that cooler temperatures affect the membrane fluidity making it more rigid and therefore more permeable to larger molecules. 25 …”

Section: Introductionmentioning

confidence: 99%

Relating structure and internalization for ROMP-based protein mimics

Backlund

Takeuchi

Futaki

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Elucidating the predominant cellular entry mechanism for protein transduction domains (PTDs) and their synthetic mimics (PTDMs) is a complicated problem that continues to be a significant source of debate in the literature. Several guanidinium-rich homopolymer structures initially designed to mimic oligoarginine, as well as an amphiphilic block copolymer, were end-labeled with FITC. This enabled the monitoring of PTDM internalization into HeLa cells by flow cytometry and confocal imaging. Additionally, their unlabeled counterparts showed improved ability to deliver proteins into cells with added hydrophobic content. In conjunction, pre-incubation with the protein is required, suggesting that the polymers are not just simply interacting with the membrane, but require association with the cargo of interest. However, the mechanism of cellular entry is not dependent on structure within this study, as punctate fluorescence was prevalent within the cells treated with fluorescently labeled samples and protein-polymer complexes. This suggests that the predominant mode of internalization for the presented PTDM structures is endosomal uptake and does not appear to be affected by concentration or structure. The PTDMs reported here provide a well-controlled platform to vary molecular composition for structure activity relationship studies to further our understanding of PTDs, their non-covalent association with cargo, and their cellular internalization pathways.

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“…Stabilized proteins may not undergo the conformational changes needed to initiate the virus infection cycle . Arginine clusters can also weaken lipid bilayers, resulting in translocation through the lipid bilayer . It is hypothesized that viral inactivation by arginine is due to protein or lipids interactions, and therefore, strengthening these interactions would increase inactivation.…”

Section: Virus Inactivation With Argininementioning

confidence: 99%

“…Loosening of lipid packing increases peptide uptake, indicating that arginine deforms the lipid bilayer for translocation . High cholesterol content in lipids decreases membrane fluidity and translocation of arginine . In the presence of the hydrophobic cation pyrenebutyrate, which is suspected to loosen lipid packing and increase membrane fluidity, arginine uptake increased in the lipid bilayer .…”

Section: Hypotheses For Synergistic Arginine Viral Inactivationmentioning

confidence: 99%

Arginine‐enveloped virus inactivation and potential mechanisms

Meingast

Heldt

2019

Biotechnology Progress

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Arginine synergistically inactivates enveloped viruses at a pH or temperature that does little harm to proteins, making it a desired process for therapeutic protein manufacturing. However, the mechanisms and optimal conditions for inactivation are not fully understood, and therefore, arginine viral inactivation is not used industrially. Optimal solution conditions for arginine viral inactivation found in the literature are high arginine concentrations (0.7–1 M), a time of 60 min, and a synergistic factor of high temperature (≥40°C), low pH (≤pH 4), or Tris buffer (5 mM). However, at optimal conditions full inactivation does not occur over all enveloped viruses. Enveloped viruses that are resistant to arginine often have increased protein stability or membrane stabilizing matrix proteins. Since arginine can interact with both proteins and lipids, interaction with either entity may be key to understanding the inactivation mechanism. Here, we propose three hypotheses for the mechanisms of arginine induced inactivation. Hypothesis 1 describes arginine‐induced viral inactivation through inhibition of vital protein function. Hypothesis 2 describes how arginine destabilizes the viral membrane. Hypothesis 3 describes arginine forming pores in the virus membrane, accompanied by further viral damage from the synergistic factor. Once the mechanisms of arginine viral inactivation are understood, further enhancement by the addition of functional groups, charges, or additives may allow the inactivation of all enveloped viruses in mild conditions.

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Translocation of cell-penetrating peptides across the plasma membrane is controlled by cholesterol and microenvironment created by membranous proteins

Cited by 65 publications

References 52 publications

Mechanism Matters: A Taxonomy of Cell Penetrating Peptides

Mechanism Matters: A Taxonomy of Cell Penetrating Peptides

Relating structure and internalization for ROMP-based protein mimics

Arginine‐enveloped virus inactivation and potential mechanisms

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