Interfacial Interactions of Hydrophobic Peptides with Lipid Bilayers

Reig, F.; Haro, Isabel; Polo, D.; Egea, M.A.; Alsina, M. A.

doi:10.1006/jcis.2001.8056

Cited by 7 publications

(10 citation statements)

References 25 publications

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“…19–21 In particular, myristate has shown promising results for membrane transport, yet only a limited number of myristoylated cargo delivery studies have been reported. 22–28 Myristoylated peptides have shown minimal adverse effects on cell viability studies, being non-toxic even up to 100 µM concentrations. 29 From a preparative standpoint, they also represent a greatly reduced synthetic burden, as only a single coupling step is required per fatty acid equivalent, in contrast to the multiple coupling steps and residues needed to assemble a functional CPP sequence.…”

Section: Resultsmentioning

confidence: 99%

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

et al. 2012

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GIPC (GAIP-interacting protein, C terminus) represents a new target class for the discovery of chemotherapeutics. While many of the current generation of anticancer agents function by directly binding to intracellular kinases or cell surface receptors, the disruption of cytosolic protein-protein interactions mediated by non-enzymatic domains is an underdeveloped avenue for inhibiting cancer growth. One such example is the PDZ domain of GIPC. Previously we developed a molecular probe, the cell permeable octapeptide CR1023 (N-myristoyl-PSQSSSEA), which diminished proliferation of pancreatic cancer cells. We have expanded upon that discovery using a chemical modification approach, and here report a series of cell permeable, side chain-modified lipopeptides that target the GIPC PDZ domain in vitro and in vivo. These peptides exhibit significant activity against pancreatic and breast cancers, both in vitro and in animal models. CR1166 (N-myristoyl-PSQSK(εN-4-bromobenzoyl)SK(εN-4-bromobenzoyl)A), bearing two halogenated aromatic units on alternate side chains, was found to be the most active compound, with pronounced down-regulation of EGFR/1GF-1R expression. We hypothesize that these organic acid-modified residues extend the productive reach of the peptide beyond the canonical binding pocket, which defines the limit of accessibility for the native proteinogenic sequences that the PDZ domain has evolved to recognize. Cell permeability is achieved with N-terminal lipidation using myristate, rather than a larger CPP (cell-penetrating peptide) sequence. This, in conjunction with optimization of targeting through side chain modification, has yielded an approach that will allow the discovery and development of next-generation cellular probes for GIPC PDZ as well as other PDZ domains.

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Section: Resultsmentioning

confidence: 99%

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

et al. 2012

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“…This degree of orientation decreases (and thus polarization increases) in an environment in which motion is restricted, i.e. a tightly packed, ordered lipid environment . Figure shows change in DPH and TMA‐DPH polarization as a function of peptide concentration when associated with PC, PC : PG, and PC : PE : SM : CHL lipid vesicles.…”

Section: Resultsmentioning

confidence: 99%

Interaction of peptides spanning the transmembrane domain of caveolin‐1 with model membranes

Lokappa

Nagaraj

2012

Journal of Peptide Science

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Caveolin-1 has an atypical membrane-spanning domain comprising of 34 residues. Caveolin-1 targets to lipid droplets under certain conditions, where they are involved in signaling and cholesterol balance. In the present study, membrane association of synthetic peptides corresponding to the membrane-spanning domain of caveolin-1 has been investigated to obtain an insight into the topology of transmembrane region in the lipid bilayer and the effect of truncations in this sequence, as observed in the targeting to lipid droplets, by using model membranes. Fluorescence studies revealed strong association of the peptide corresponding to the membrane-spanning domain of caveolin-1 with anionic lipids as compared with zwitterionic lipids, which is consistent with the location of this domain in the cytoplasmic side of the plasma membrane. Association of a short 9 residue peptide corresponding to the C-terminus of caveolin-1 membrane-spanning domain with lipid vesicles revealed the importance of this region for association with model membranes. Our investigations indicate that the peptide corresponding to the membrane-spanning domain of caveolin-1 does not span the lipid bilayer. We propose that both caveolin scaffolding domain and transmembrane segment of caveolin-1 contribute to the strong association with the plasma membrane rendering the protein highly detergent resistant.

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“…Lipidated analogues of the pentapeptide YIGSR-NH 2 (Fig. 5a) showed weak disturbances in dipalmitoylphosphatidylcholine (DPPC) liposome bilayers due to the similarity of peptide lipid chains with DPPC lipid chains [107]. The interactions also affect the membrane trafficking, localization and signal transduction of lipidated peptides, as indicated in Ras proteins [108,109].…”

Section: Membrane Bindingmentioning

confidence: 98%

Converting Peptides into Drug Leads by Lipidation

Zhang¹,

Bułaj²

2012

CMC

175

139

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Ulceration in the gastrointestinal (GI) mucosa is a common disorder in humans. It has been shown that cigarette smoking is closely related to the increase of peptic ulcer and also plays an inhibitory role on ulcer healing. However, the underlying mechanisms by which cigarette smoke exerts these adverse effects remain largely unknown. It is perhaps partly due to the complexity of chemical compositions in the smoke and furthermore their pathological actions are largely undefined. In this review, we have highlighted the potential adverse effects of the toxic chemical components in cigarette smoke and summarized their possible mechanisms of actions on ulcer formation and healing in the GI tract. We also discuss in detail how cigarette smoke disturbs cell proliferation, influences mucus synthesis and secretion, delays blood vessel formation, and interferes the innate immune responses during ulceration and repair in the GI mucosa.

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Interfacial Interactions of Hydrophobic Peptides with Lipid Bilayers

Cited by 7 publications

References 25 publications

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

Chemically Modified Peptides Targeting the PDZ Domain of GIPC as a Therapeutic Approach for Cancer

Interaction of peptides spanning the transmembrane domain of caveolin‐1 with model membranes

Converting Peptides into Drug Leads by Lipidation

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