Cell Penetrating Peptides: How Do They Do It?

Herce, Henry D.; Garcı́a, Angel E.

doi:10.1007/s10867-008-9074-3

Cited by 94 publications

(112 citation statements)

References 65 publications

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…On the basis of these results, we suggest that hLF1-11 comprises two regions that are important for its ability to inhibit the enzymatic activity of MPO; that is, the arginines that bind to the crevice of the active site by electrostatic interactions and the cysteine that interferes with ROS. In addition, the arginines may mediate binding to and entry into cells (26,27). Together, our results with human monocytes and (immobilized) MPO indicate that hLF1-11 inhibits the enzymatic activities of both intracellular and extracellular MPO.…”

Section: Discussionsupporting

confidence: 51%

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

Does

Hensbergen

Bogaards

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Because of their ability to eliminate pathogens and to modulate various host immune responses, antimicrobial peptides are considered as candidate agents to fight infections by (antibiotic-resistant) pathogens. We recently reported that hLF1-11 (GRRRRSVQWCA), an antimicrobial peptide derived from the N terminus of human lactoferrin, displays diverse modulatory activities on monocytes, thereby enhancing their actions in innate immune responses. The aim of this study was to identify the cellular target of hLF1-11 that mediates these effects. Results revealed that hLF1-11 binds and subsequently penetrates human monocytes, after which it inhibits the enzymatic activities of myeloperoxidase (MPO). Moreover, a chemical inhibitor of MPO (aminobenzoic acid hydrazide) mimicked the effects of hLF1-11 on the inflammatory response by monocytes and on monocyte–macrophage differentiation. Computer-assisted molecular modeling predicted that hLF1-11 can bind to the edge of and within the crevice of the active site of MPO. Experiments with a set of hLF1-11 peptides with amino acid substitutions identified the stretch of arginines and the cysteine at position 10 as pivotal in these immunomodulatory properties of hLF1-11. We conclude that hLF1-11 may exert its modulatory effects on human monocytes by specific inhibition of MPO activity.

show abstract

Section: Discussionsupporting

confidence: 51%

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

Does

Hensbergen

Bogaards

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Due to the relatively flat diffusion coefficient profiles and the similarity of the D(z) values for the three peptides, the differences in passive diffusion rates are mostly determined by the free energy profiles. 39 The calculated passage times are systematically lower and the permeability coefficients are systematically higher than our experimentally measured values for all three peptides. The calculated permeation times differ by many orders of magnitude.…”

Section: Permeability Measuresmentioning

confidence: 49%

“…18,43,44,87,89,90 Others hypothesize that membrane and solvent structural fluctuations play an important role as well. 39,85 The CHARMM lipid force field also overestimates the electric field strength within the membrane by a factor of 3, which may be lowering the value of the PMF within the membrane interior and subsequently accelerating the mean passage time. 63 The discrepancy between our experimental and theoretical results can be attributed to any or all of the above concerns.…”

Section: Permeability Measuresmentioning

confidence: 99%

“…14 Recent molecular dynamics studies have focused on a wide variety of molecules passively diffusing through membranes, such as water, [15][16][17] small molecules, [18][19][20][21][22][23] model drug compounds, 6,22,24,25 analgesics, [26][27][28] drug delivery systems, 29,30 dyes, 31,32 other lipids, 33,34 nanoparticles, [35][36][37] toxins, 38 small peptides, 39,40 and even transmembrane proteins. 41,42 However, only a handful of MD studies have examined amino acid-related systems and are confined to tryptophan, [43][44][45] arginine, 46,47 lysine, 47 and amino acid analogues.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Lee

Kuczera

Middaugh

et al. 2016

The Journal of Chemical Physics

View full text Add to dashboard Cite

The time-resolved parallel artificial membrane permeability assay with fluorescence detection and comprehensive computer simulations are used to study the passive permeation of three aromatic dipeptides—N-acetyl-phenylalanineamide (NAFA), N-acetyltyrosineamide (NAYA), and N-acetyl-tryptophanamide (NATA) through a 1,2-dioleoyl-sn-glycero-3-phospocholine (DOPC) lipid bilayer. Measured permeation times and permeability coefficients show fastest translocation for NAFA, slowest for NAYA, and intermediate for NATA under physiological temperature and pH. Computationally, we perform umbrella sampling simulations to model the structure, dynamics, and interactions of the peptides as a function of z, the distance from lipid bilayer. The calculated profiles of the potential of mean force show two strong effects—preferential binding of each of the three peptides to the lipid interface and large free energy barriers in the membrane center. We use several approaches to calculate the position-dependent translational diffusion coefficients D(z), including one based on numerical solution the Smoluchowski equation. Surprisingly, computed D(z) values change very little with reaction coordinate and are also quite similar for the three peptides studied. In contrast, calculated values of sidechain rotational correlation times τrot(z) show extremely large changes with peptide membrane insertion—values become 100 times larger in the headgroup region and 10 times larger at interface and in membrane center, relative to solution. The peptides’ conformational freedom becomes systematically more restricted as they enter the membrane, sampling α and β and C7eq basins in solution, α and C7eq at the interface, and C7eq only in the center. Residual waters of solvation remain around the peptides even in the membrane center. Overall, our study provides an improved microscopic understanding of passive peptide permeation through membranes, especially on the sensitivity of rotational diffusion to position relative to the bilayer.

show abstract

“…For the TAT protein to carry out its biological functions, it needs to be readily imported into the cell. Studies on the cellular internalization of TAT have led to the discovery of the TAT peptide, a highly cationic 11-aa region (protein transduction domain) of the 86-aa full-length protein that is responsible for the TAT protein translocating across phospholipid membranes (5)(6)(7)(8). The TAT peptide is a member of a class of peptides called cell-penetrating peptides (CPPs) that have generated great interest for drug delivery applications (ref.…”

mentioning

confidence: 99%

Label-free probe of HIV-1 TAT peptide binding to mimetic membranes

Rao

Kwok

Lombardi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The transacting activator of transduction (TAT) protein plays a key role in the progression of AIDS. Studies have shown that a +8 charged sequence of amino acids in the protein, called the TAT peptide, enables the TAT protein to penetrate cell membranes. To probe mechanisms of binding and translocation of the TAT peptide into the cell, investigators have used phospholipid liposomes as cell membrane mimics. We have used the method of surface potential sensitive second harmonic generation (SHG), which is a label-free and interface-selective method, to study the binding of TAT to anionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-1′-rac-glycerol (POPG) and neutral 1-palmitoyl-2-oleoylsn-glycero-3-phosphocholine (POPC) liposomes. It is the SHG sensitivity to the electrostatic field generated by a charged interface that enabled us to obtain the interfacial electrostatic potential. SHG together with the Poisson-Boltzmann equation yielded the dependence of the surface potential on the density of adsorbed TAT. We obtained the dissociation constants K d for TAT binding to POPC and POPG liposomes and the maximum number of TATs that can bind to a given liposome surface. For POPC K d was found to be 7.5 ± 2 μM, and for POPG K d was 29.0 ± 4.0 μM. As TAT was added to the liposome solution the POPC surface potential changed from 0 mV to +37 mV, and for POPG it changed from −57 mV to −37 mV. A numerical calculation of K d , which included all terms obtained from application of the Poisson-Boltzmann equation to the TAT liposome SHG data, was shown to be in good agreement with an approximated solution.Gouy-Chapman model | hyper-Rayleigh scattering | biomolecules/water interface | colloid/water interface | nonlinear optical spectroscopy T he HIV type 1 (HIV-1) transacting activator of transduction (TAT) is an important regulatory protein for viral gene expression (1-3). It has been established that the TAT protein has a key role in the progression of AIDS and is a potential target for anti-HIV vaccines (4). For the TAT protein to carry out its biological functions, it needs to be readily imported into the cell. Studies on the cellular internalization of TAT have led to the discovery of the TAT peptide, a highly cationic 11-aa region (protein transduction domain) of the 86-aa full-length protein that is responsible for the TAT protein translocating across phospholipid membranes (5-8). The TAT peptide is a member of a class of peptides called cell-penetrating peptides (CPPs) that have generated great interest for drug delivery applications (ref. 9 and references therein). The exact mechanism by which the TAT peptide enters cells is not fully understood, but it is likely to involve a combination of energy-independent penetration and endocytosis pathways (8, 10). The first step in the process is high-affinity binding of the peptide to phospholipids and other components on the cell surface such as proteins and glycosaminoglycans (1, 9).The binding of the TAT peptide to liposomes has been investigated using a variety of techniques, each...

show abstract

Cell Penetrating Peptides: How Do They Do It?

Cited by 94 publications

References 65 publications

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

The Human Lactoferrin-Derived Peptide hLF1-11 Exerts Immunomodulatory Effects by Specific Inhibition of Myeloperoxidase Activity

Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Label-free probe of HIV-1 TAT peptide binding to mimetic membranes

Contact Info

Product

Resources

About