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May 6, 2015
Increasing AIP Macrocycle Size Reveals Key Features of agr Activation in Staphylococcus aureus.

Chembiochem. 2015 May 4;16(7):1093-100. doi: 10.1002/cbic.201500006. Epub 2015 Mar 20.

Johnson JG1, Wang B, Debelouchina GT, Novick RP, Muir TW.

1Department of Chemistry, Princeton University, Frick Chemistry Building, Washington Road, Princeton, NJ 08544 (USA); Graduate Program, The Rockefeller University, 1230 York Avenue, New York, NY 10065 (USA); Tri-Institutional Training Program in Chemical Biology, Weil-Cornell/Memorial Sloan Kettering/Rockefeller University, New York, NY 10065 (USA).

Abstract

The agr locus in the commensal human pathogen, Staphylococcus aureus, is a two-promoter regulon with allelic variability that produces a quorum-sensing circuit involved in regulating virulence within the bacterium. Secretion of unique autoinducing peptides (AIPs) and detection of their concentrations by AgrC, a transmembrane receptor histidine kinase, coordinates local bacterial population density with global changes in gene expression. The finding that staphylococcal virulence can be inhibited through antagonism of this quorum-sensing pathway has fueled tremendous interest in understanding the structure-activity relationships underlying the AIP-AgrC interaction. The defining structural feature of the AIP is a 16-membered, thiolactone-containing macrocycle. Surprisingly, the importance of ring size on agr activation or inhibition has not been explored. In this study, we address this deficiency through the synthesis and functional analysis of AIP analogues featuring enlarged and reduced macrocycles. Notably, this study is the first to interrogate AIP function by using both established cell-based reporter gene assays and newly developed in vitro AgrC-I binding and autophosphorylation activity assays. Based on our data, we present a model for robust agr activation involving a cooperative, three-points-of-contact interaction between the AIP macrocycle and AgrC.

 

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May 6, 2015
A promising future for peptides in ophthalmology: work effectively and smartly.

Curr Med Chem. 2015;22(8):1030-40.

Sun Q, Xu X1.

Author information

  • 1Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiaotong University, No. 100, Haining Road, Shanghai, People's Republic of China. drxuxun@sjtu.edu.cn.

Abstract

Despite progress in pharmacological modalities, treatments for ocular diseases are inconvenient, traumatic, costly and often end in poor final visual results. Peptides, considered as protein fragments, can adequately mimic protein binding and thus are used as therapeutic agents. Chemical modifications and bioengineering techniques are being frequently introduced to improve efficacy and stability of peptides, thereby improving their druggability. Cell-penetrating peptides (CPPs), peptides characterized by penetrating plasma membrane, are famous barrier- passers. They are good candidates for carrying drugs through ocular barriers. Therapeutic peptide and CPP perfectly complement each other. Once united, they may form an optimal formula for ocular topical administration, which can work both effectively and smartly. The consequent noninvasive delivery and economical cost would actualize prophylactic intervention, early treatment and long-term therapy to avoid chronic irreversible vision loss. The aim of the current review is a) to summarize recent therapeutic peptides, both anti-angiogenic and anti-inflammation, evidenced by animal experiments in vivo; b) to discuss the discovery strategies for therapeutic peptide; c) to present current delivery strategies for ophthalmic therapeutic peptide; and d) to introduce CPPs which are capable to deliver cargos to intraocular space via ocular surface administration.

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May 6, 2015
Early engineering approaches to improve peptide developability and manufacturability.

AAPS J. 2015 Jan;17(1):111-20

Furman JL1, Chiu M, Hunter MJ.

1Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, California, 92121, USA.

Abstract

Downstream success in Pharmaceutical Development requires thoughtful molecule design early in the lifetime of any potential therapeutic. Most therapeutic monoclonal antibodies are quite similar with respect to their developability properties. However, the properties of therapeutic peptides tend to be as diverse as the molecules themselves. Analysis of the primary sequence reveals sites of potential adverse posttranslational modifications including asparagine deamidation, aspartic acid isomerization, methionine, tryptophan, and cysteine oxidation and, potentially, chemical and proteolytic degradation liabilities that can impact the developability and manufacturability of a potential therapeutic peptide. Assessing these liabilities, both biophysically and functionally, early in a molecule's lifetime can drive a more effective path forward in the drug discovery process. In addition to these potential liabilities, more complex peptides that contain multiple disulfide bonds can pose particular challenges with respect to production and manufacturability. Approaches to reducing the disulfide bond complexity of these peptides are often explored with mixed success. Proteolytic degradation is a major contributor to decreased half-life and efficacy. Addressing this aspect of peptide stability early in the discovery process increases downstream success. We will address aspects of peptide sequence analysis, molecule complexity, developability analysis, and manufacturing routes that drive the decision making processes during peptide therapeutic development.

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May 5, 2015
The human T-cell repertoire grows up

T-cell repertoire

The human T-cell repertoire grows up

James J Moon1,2,3 and Marc K Jenkins4

  1. 1Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
  2. 2Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA
  3. 3Harvard Medical School; Boston, MA, USA
  4. 4Center for Immunology and Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA

Correspondence: Marc K Jenkins, E-mail: jenki002@umn.edu

To recognize major histocompatibility complex (MHC)-bound peptides from virtually any intracellular antigen, the adaptive immune system develops a vast pre-immune repertoire of T-cell clones, each with one of a seemingly infinite number of unique T-cell antigen receptors (TCRs). Studies in inbred mice have revealed several features of this repertoire.1, 2, 3, 4 First, the number of naive T cells that recognize a given MHC-bound foreign peptide is small, on the order of 1 cell per million, and consistent among genetically identical individuals. Second, the number of naive T cells that recognize one MHC-bound foreign peptide is likely to differ from the number that recognize another. And third, the number of naive T cells that recognize an MHC-bound foreign peptide correlates with the number of effector and memory cells produced during a primary immune response. Although some studies have been done in humans,5, 6 it is not yet clear whether the repertoire will be more complicated in humans due to MHC polymorphisms and extensive pathogen exposure.

In this issue of ICB, Neller et al.7 study the evolution of peptide:MHCI epitope-specific CD8+ T-cell populations in humans using cross-sectional evaluations of naive T-cell populations in umbilical cord blood and memory T-cell populations in adult blood. Using peptide:MHC multimer-based cell enrichment techniques, they enumerate CD8+ T cells specific for viral peptide:MHCI epitopes at birth, and show that these cells increase dramatically following antigen exposure in adulthood. By performing TCR-sequencing analysis, they observe a concomitant decrease in the TCR clonal diversity of T cells within these populations.

The use of umbilical cord blood samples provided an effective means of characterizing the initial frequency and clonal diversity of epitope-specific naive T-cell populations as they emerge from the human thymus and likely before any exposure to foreign antigens. This is not a trivial concern, as many foreign epitope-specific T cells in people who have never been exposed to that epitope have a memory cell phenotype5 perhaps due to homeostatic proliferation8 or cross-reactivity to similar peptides from environmental antigens.2, 9 Moreover, extrathymic proliferation is thought to have a major role in the maintenance of the naive T-cell pool in humans.10 By examining six different peptide:MHCI-specific CD8+ T-cell populations in human leukocyte antigen matched subjects, the authors found that like in mice, the number of naive T cells differed for different peptide:MHC ligands, and these frequencies were consistent across several individuals. This result suggests that MHC-driven selection is the main determinant of epitope-specific naive T-cell numbers in mouse secondary lymphoid organs and human cord blood.

Surprisingly, the hierarchy of T-cell frequencies for different viral epitopes was lost in peripheral blood samples from virus-seropositive subjects, indicating that clonal expansion was not proportional to the number of naive T cells in cord blood. Thus, variables other than naive T-cell frequency may determine the magnitude of the primary response, at least for certain peptides.11 It is also possible, however, that the naive T-cell frequencies for different viral epitopes changed between the time of birth and the time of viral infection. Indeed, the authors found that naive T-cell frequencies for two different viral epitopes in unexposed adults aligned with those in exposed adult blood rather than those in cord blood. Although it is not possible to reach a definitive conclusion with this limited sample, the results suggest the intriguing possibility that the naive T-cell frequency for a given foreign peptide:MHC epitope can change after birth by a process that does not involve direct recognition of that epitope. It is possible that certain clones in the population undergo homeostatic proliferation in response to interleukin-7 and a self peptide:MHC ligand, or in response to an MHC-bound foreign peptide with a related amino-acid sequence from an environmental antigen (Figure 1). The authors also reveal a winnowing of the TCR repertoire within all of the viral epitope-specific populations after infection, with a surprising loss of some public T-cell clones in some populations. This supports the presence of a competitive environment causing the selective loss of certain clonotypes, which is expected during the course of an immune response. However, it remains to be seen whether such selective processes are in effect during the period between birth and adulthood before the onset of the cognate immune response.

Figure 1.

Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the authorModel for repertoire change before exposure to foreign antigen. The figure depicts a cord blood repertoire of three T-cell clones each with a different TCR specific for slightly different conformations of the same MHC-bound peptide from virus X. All three clones have the naive cell surface phenotype. Sometime during adulthood, the host is exposed to a virus that has a peptide that is structurally homologous to the virus X peptide conformation recognized by clone 1 or a Virus X-like self peptide and IL-7, which causes clone 1 to proliferate and adopt the memory cell surface phenotype. Later in life the host is infected with virus X and all three clones proliferate and form memory cells. Note that clone 1 is overrepresented in the resulting memory cell pool compared with its frequency in cord blood.

Full figure and legend (103K)


Collectively, this study highlights the power of analyzing cord blood samples to define a true baseline repertoire of epitope-specific T cells in humans. In doing so, it raises interesting new questions about how epitope-specific naive T-cell populations evolve during the long lifespans of humans.

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References

  1. Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM et al. Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 2007; 27: 203–213. | Article | PubMed | ISI | CAS |
  2. Nelson RW, Beisang D, Tubo NJ, Dileepan T, Wiesner DL, Nielsen K et al. T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity. Immunity 2015; 42: 95–107. | Article | PubMed | ISI |
  3. Haluszczak C, Akue AD, Hamilton SE, Johnson LD, Pujanauski L, Teodorovic Let al. The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion.J Exp Med 2009; 206: 435–448. | Article | PubMed | ISI | CAS |
  4. Obar JJ, Khanna KM, Lefrancois L. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity2008; 28: 859–869. | Article | PubMed | CAS |
  5. Su LF, Kidd BA, Han A, Kotzin JJ, Davis MM. Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults. Immunity 2013; 38: 373–383. | Article | PubMed | ISI | CAS |
  6. Campion SL, Brodie TM, Fischer W, Korber BT, Rossetti A, Goonetilleke N et al. Proteome-wide analysis of HIV-specific naive and memory CD4(+) T cells in unexposed blood donors. J Exp Med 2014; 211: 1273–1280. | Article | PubMed | ISI |
  7. Neller MA, Ladell K, McLaren JE, Matthews KK, Gostick E, Pentier JM et al. Naïve CD8+ T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics. Immunol Cell Biol (e-pub ahead of print 24 March 2015; doi:10.1038/icb.2015.17). | Article |
  8. Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity2008; 29: 848–862. | Article | PubMed | ISI | CAS |
  9. Birnbaum ME, Mendoza JL, Sethi DK, Dong S, Glanville J, Dobbins J et al. Deconstructing the peptide-MHC specificity of T cell recognition. Cell 2014;157: 1073–1087. | Article | PubMed | ISI | CAS |
  10. den Braber I, Mugwagwa T, Vrisekoop N, Westera L, Mögling R, de Boer AB et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 2012; 36: 288–297. | Article | PubMed | ISI | CAS |
  11. La Gruta NL, Rothwell WT, Cukalac T, Swan NG, Valkenburg SA, Kedzierska Ket al. Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion. J Clin Invest 2010;120: 1885–1894. | Article | PubMed | ISI | CAS |
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March 30, 2015
Effects and mechanisms of the secondary structure on the antimicrobial activity and specificity of antimicrobial peptides

A 15-mer cationic α-helical antimicrobial peptide HPRP-A1 was used as the parent peptide to study the effects of peptide secondary structure on the biophysical properties and biological activities. Without changing the amino acid composition of HPRP-A1, we designed two α-helical peptides with either higher or lower helicity compared with the parent peptide, a β-sheet peptide and a random coiled peptide using de novo design approach. The secondary structures were confirmed by circular dichroism spectroscopy. The three α-helical peptides exhibited comparable antibacterial activities, but their hemolytic activity varied from extreme hemolysis to no hemolysis, which is correlated with their helicity. The β-sheet peptide shows poor antibacterial and strong hemolytic activities. More interestingly, the random coil peptide shows no antibacterial activity against Gram-negative bacteria, weak antibacterial activity against Gram-positive bacteria, and extremely weak hemolytic activity. Bacterial membrane permeabilization was also testified on peptides with different secondary structures. Tryptophan fluorescence experiment revealed that the peptide binding preference to the lipid vesicles for mimicking the prokaryotic or eukaryotic membranes was consistent with their biological activities. With the de novo design approach, we proved that it is important to maintain certain contents of amphipathic secondary structure for a desirable biological activity. We believe that the de novo design approach of relocation of the amino acids within a template sequence could be an effective approach in optimizing the specificity of an antimicrobial peptide. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

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Peptide structure of HPRP-A1 was artificially altered without changing the amino acid composition. Peptide secondary structure alone plays a crucial role on peptide biological activities without the effects of other parameters. The de novo design approach of relocation of the amino acids within a template sequence could be an effective approach in optimizing the specificity of an antimicrobial peptide.

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March 26, 2015
Synthesis of diastereomerically pure Lys(Nε-lipoyl) building blocks and their use in Fmoc/tBu solid phase synthesis of lipoyl-containing peptides for diagnosis of primary biliary cirrhosis

Primary Biliary Cirrhosis is an immune-mediated disease in which one of the epitopes recognized by antimitochondrial autoantibodies is a lipoylated fragment of the PDC-E2 protein. Accordingly, the synthesis of lipoylated peptides as diagnostic tools is a relevant target. Up to now, the proper tools for the introduction of lipoylation on building blocks to be used in Fmoc/tBu solid phase peptide synthesis (SPPS) are lacking, and the role of chirality in lipoylation remains poorly studied.

In this paper, we present the synthesis of lipoylated lysine derivatives as pure diastereomeric building blocks suitable for Fmoc/tBu SPPS and their introduction in relevant peptide sequences to possibly serve as synthetic probes for the development of novel diagnostic tools for this disease.

The optimization of the synthesis of lipoylated building blocks derived from racemic, (R)-, and (S)-α-lipoic acid is described. Synthesis of peptide probes incorporating lipoylation is described. An insight regarding the cleavage of lipoylated peptides is given, as well as a method to oxidize or reduce the 1,2-dithiolane ring of the lipoyl moiety directly on the peptide without any subsequent purification. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

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Primary Biliary Cirrhosis is an immune-mediated disease, in which the epitope recognized by autoantibodies is a lipoylated fragment of the PDC-E2 protein. In this paper, we present the synthesis of lipoylated lysines as pure diastereomeric building blocks suitable for Fmoc/tBu solid phase peptide synthesis (SPPS) and their introduction in relevant peptidic sequences to possibly serve as synthetic probes for molecular diagnostic of this disease.

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March 25, 2015
Antimicrobial benzodiazepine-based short cationic peptidomimetics

Antimicrobial peptides (AMPs) appear to be good candidates for the development of new antibiotic drugs. We describe here the synthesis of peptidomimetic compounds that are based on a benzodiazepine scaffold flanked with positively charged and hydrophobic amino acids. These compounds mimic the essential properties of cationic AMPs. The new design possesses the benzodiazepine scaffold that is comprised of two glycine amino acids and which confers flexibility and aromatic hydrophobic ‘back’, and two arms used for further synthesis on solid phase for incorporation of charged and hydrophobic amino acids. This approach allowed us a better understanding of the influence of these features on the antimicrobial activity and selectivity. A novel compound was discovered which has MICs of 12.5 µg/ml against Staphylococcus aureus and 25 µg/ml against Escherichia coli, similar to the well-known antimicrobial peptide MSI-78. In contrast to MSI-78, the above mentioned compound has lower lytic effect against mammalian red blood cells. These peptidomimetic compounds will pave the way for future design of potent synthetic mimics of AMPs for therapeutic and biomedical applications. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

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Peptidomimetic compounds based on a benzodiazepine scaffold flanked with positive and hydrophobic amino acids were synthesized, mimicking the essential properties of cationic antimicrobial peptides (AMPs). One compound exhibited MICs of 12.5 µg/mL against S. Aureus and 25 µg/mL against E. Coli, with very low hemolytic effect. These compounds may pave the way for future potent synthetic mimics of antimicrobial peptides (SMAMPs) for therapeutic applications.

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March 24, 2015
Engineering of a linear inactive analog of human β-defensin 4 to generate peptides with potent antimicrobial activity

Human β-defensins (HBDs) are cationic antimicrobial peptides constrained by three disulfide bridges. They have diverse range of functions in the innate immune response. It is of interest to investigate whether linear analogs of defensins can be generated, which possess antimicrobial activity. In this study, we have designed linear peptides with potent antimicrobial activity from an inactive peptide spanning the N-terminus of HBD4. Our results show that l-arginine to d-arginine substitution imparts considerable antimicrobial activity against both bacteria and Candida albicans. Increase in hydrophobicity by fatty acylation of the peptides with myristic acid further enhances their potency. In the presence of high concentrations of salt, antimicrobial activity of the myristoylated peptide with l-arginine is attenuated relatively to a lesser extent as compared with the linear active peptide with d-arginine. Substitution of cysteine with the hydrophobic helix-promoting amino acid α-aminoisobutyric acid favors candidacidal activity but not antibacterial activity. The mechanism of killing by d-arginine substituted unacylated analog involves transient interaction with the bacterial membrane followed by translocation into the cytoplasm without membrane permeabilization. Accumulation of peptides in the cytoplasm can affect various cellular processes that lead to cell death. However, the peptide causes membrane permeabilization in case of C. albicans. Myristoylation results in greater interaction of the peptide chain with the microbial cell surface and causes membrane permeabilization. Results described in the study demonstrate that it is possible to generate highly active linear analogs of defensins by selective introduction of d-amino acids and fatty acids, which could be attractive candidates for development as therapeutic agents. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

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Peptides with antimicrobial activity were generated from an inactive linear peptide derived from human β-defensin 4. Active peptide was generated by selective R to DR substitution. N-terminal myristoylation resulted in further enhancement of activity. Mechanism of killing did not involve detergent-like action on the membranes.

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March 23, 2015
B-type natriuretic peptide expression and cardioprotection is regulated by Akt dependent signaling at early reperfusion

Publication date: April 2015 Source:Peptides, Volume 66
Author(s): L. Breivik , A. Jensen , S. Guvåg , E.K. Aarnes , A. Aspevik , E. Helgeland , S. Hovland , T. Brattelid , A.K. Jonassen
Exogenously administered B-type natriuretic peptide (BNP) has been shown to offer cardioprotection through activation of particulate guanylyl cyclase (pGC), protein kinase G (PKG) and KATP channel opening. The current study explores if cardioprotection afforded by short intermittent BNP administration involves PI3K/Akt/p70s6k dependent signaling, and whether this signaling pathway may participate in regulation of BNP mRNA expression at early reperfusion. Isolated Langendorff perfused rat hearts were subjected to 30min of regional ischemia and 120min of reperfusion (IR). Applying intermittent 3×30s infusion of BNP peptide in a postconditioning like manner (BNPPost) reduced infarct size by >50% compared to controls (BNPPost 17±2% vs. control 42±4%, p <0.001). Co-treatment with inhibitors of the PI3K/Akt/p70s6k pathway (wortmannin, SH-6 and rapamycin) completely abolished the infarct-limiting effect of BNP postconditioning (BNPPost +Wi 36±5%, BNPPost +SH-6 41±4%, BNPPost +Rap 37±6% vs. BNPPost 17±2%, p <0.001). Inhibition of natriuretic peptide receptors (NPR) by isatin also abrogated BNPPost cardioprotection (BNPPost +isatin 46±2% vs. BNPPost 17±2%, p <0.001). BNPPost also significantly phosphorylated Akt and p70s6k at early reperfusion, and Akt phosphorylation was inhibited by SH-6 and isatin. Myocardial BNP mRNA levels in the area at risk (AA) were significantly elevated at early reperfusion as compared to the non-ischemic area (ANA) (Ctr(AA) 2.7±0.5 vs. Ctr(ANA) 1.2±0.2, p <0.05) and the ischemic control tissue (Ctr(AA) 2.7±0.5 vs. ischemia 1.0±0.1, p <0.05). Additional experiments also revealed a significant higher BNP mRNA level in ischemic postconditioned (IPost) hearts as compared to ischemic controls (IPost 6.7±1.3 vs. ischemia 1.0±0.2, p <0.05), but showed no difference from controls run in parallel (Ctr 5.4±0.8). Akt inhibition by SH-6 completely abrogated this elevation (IPost 6.7±1.3 vs. IPost+SH-6 1.8±0.7, p <0.05) (Ctr 5.4±0.8 vs. SH-6 1.5±0.9, p <0.05). In conclusion, Akt dependent signaling is involved in mediating the cardioprotection afforded by intermittent BNP infusion at early reperfusion, and may also participate in regulation of reperfusion induced BNP expression.

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March 18, 2015
When cationic cell-penetrating peptides meet hydrocarbons to enhance in-cell cargo delivery

Cell-penetrating peptides (CPPs) are short sequences often rich in cationic residues with the remarkable ability to cross cell membranes. In the past 20 years, CPPs have gained wide interest and have found numerous applications in the delivery of bioactive cargoes to the cytosol and even the nucleus of living cells. The covalent or non-covalent addition of hydrocarbon moieties to cationic CPPs alters the hydrophobicity/hydrophilicity balance in their sequence. Such perturbation dramatically influences their interaction with the cell membrane, might induce self-assembling properties and modifies their intracellular trafficking. In particular, the introduction of lipophilic moieties changes the subcellular distribution of CPPs and might result in a dramatically increase of the internalization yield of the co-transported cargoes. Herein, we offer an overview of different aspects of the recent findings concerning the properties of CPPs covalently or non-covalently associated to hydrocarbons. We will focus on the impact of the hydrocarbon moieties on the delivery of various cargoes, either covalently or non-covalently bound to the modified CPPs. We will also provide some key elements to rationalize the influence of the hydrocarbons moieties on the cellular uptake. Furthermore, the recent in vitro and in vivo successful applications of acylated CPPs will be summarized to provide a broad view of the versatility of these modified CPPs as small-molecules and oligonucleotides vectors. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

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The influence of hydrocarbon moieties on the internalization and delivery ability of cell-penetrating peptides is reviewed. The alterations of their physico-chemical characteristics are discussed in order to rationalize some of the emerging properties of cell-penetrating lipopeptides. General rules for the design of new lipopeptides are outlined as well as a guideline to choose the appropriate delivery vector.

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