Lipidic peptides. VIII. Cellular uptake studies of lipidic amino acid, its oligomers and highly lipophilic drug conjugates

Tóth, István; Griffith, I P; Olmo, Esther del; Hafeez, Rafeeda A.; Holley, Jane L.; Ward, Pamela; Gibbons, William A.

doi:10.1016/0378-5173(92)90091-f

Cited by 9 publications

(4 citation statements)

References 9 publications

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“…Although not as commonly employed as cell-penetrating peptides (CPPs), there are various examples in the literature for lipidated peptides and lipophilic drug conjugates being used as drug delivery systems. 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.…”

Section: Resultsmentioning

confidence: 99%

“…The peptides were designed so that a myristoyl fatty acid, a saturated 14-carbon alkyl acid, would function as the cargo delivery system. Although not as commonly employed as cell-penetrating peptides (CPPs), there are various examples in the literature for lipidated peptides and lipophilic drug conjugates being used as drug delivery systems. − In particular, myristate has shown promising results for membrane transport, yet only a limited number of myristoylated cargo delivery studies have been reported. − Myristoylated peptides have shown minimal adverse effects on cell viability studies, being non-toxic even up to 100 μM concentrations . 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%

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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%

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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“…Lipidic amino acids have been attached covalently to polar drugs in an attempt to enhance their bioavailability. − ,,− In this work we have covalently attached the fluorescent moiety 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) to the α-amine group of compound 4 (NBD-C 13 AA). The resulting secondary amine is expected to be a very weak base, and therefore, in aqueous solutions at pH = 7.4, NBD-C 13 AA has a negative charge.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Characterization of a Lipidic Alpha Amino Acid: Solubility and Interaction with Serum Albumin and Lipid Bilayers

et al. 2013

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The lipidic α-amino acid with 11 carbons in the alkyl lateral chain (α-aminotridecanoic acid) was synthesized via multicomponent hydroformylation/Strecker reaction, which is a greener synthetic approach to promote this transformation relative to previously described methods. Its solubility and aggregation behavior in aqueous solutions was characterized, as well as the interaction with lipid bilayers. Lipidic amino acids are very promising molecules in the development of prodrugs with increased bioavailability due to the presence of the two polar functional groups and nonpolar alkyl chain. They are also biocompatible surfactants that may be used in the food and pharmaceutical industry. In this work we have conjugated the lipidic amino acid with a fluorescent polar group (7-nitrobenz-2-oxa-1,3-diazol-4-yl), to mimic drug conjugates, and its association with serum proteins and lipid bilayers was characterized. The results obtained indicate that conjugates of polar molecules with lipidic α-amino acid, via covalent attachment to the amine group, have a relatively high solubility in aqueous solutions due to their negative global charge. They bind to serum albumin with intermediate affinity and show a very high partition coefficient into lipid bilayers in the liquid-disordered state. The attachment of the polar group to the lipidic amino acid increased strongly the aqueous solubility of the amphiphile, although the partition coefficient into lipid membranes was not significantly reduced. Conjugation of polar drugs with lipidic amino acids is therefore an efficient approach to increase their affinity for biomembranes.

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“…In CPPS these modifications could alter the aforementioned balance and favor their interaction with the cell membrane (16). Lipidic peptides and lipophilic drug conjugates have been applied in drug delivery systems, modifying in some cases the intracellular pathway (17–19).…”

Section: Introductionmentioning

confidence: 99%

Fatty acyl moieties: improving Pro‐rich peptide uptake inside HeLa cells

Fernández‐Carneado

Kogan

Mau

et al. 2005

The Journal of Peptide Research

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In the field of drug delivery there has been a continuous study of powerful delivery systems to aid non permeable drugs in reaching their intracellular target. Among the systems explored are cell penetrating peptides (CPPs), which first garnered interest a decade ago when the interesting translocation properties of the pioneer CPPs Tat and Antp were described. A new family of CPPs has recently been described as non cytotoxic Pro-rich vectors with favorable profiles for internalization in HeLa cells. Fatty acyl moieties that can tune a peptide's interaction with the lipophilic environment of a cell membrane have been incorporated into the Pro-rich sequence. Improvements in cellular uptake of peptides modified with fatty acyl groups, as studied by confocal microscopy and flow cytometry, as well as the results obtained by the interaction of these peptides with a model dioleoylphosphatidylcholine (DOPC) membrane and transmission electron microscopy (TEM), illustrate the importance of the fatty acyl moieties for efficient internalization.

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Lipidic peptides. VIII. Cellular uptake studies of lipidic amino acid, its oligomers and highly lipophilic drug conjugates

Cited by 9 publications

References 9 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

Synthesis and Characterization of a Lipidic Alpha Amino Acid: Solubility and Interaction with Serum Albumin and Lipid Bilayers

Fatty acyl moieties: improving Pro‐rich peptide uptake inside HeLa cells

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