Emtricitabine Prodrugs with Improved Anti-HIV Activity and Cellular Uptake

Agarwal, Hitesh K.; Chhikara, Bhupender S.; Bhavaraju, Sitaram; Mandal, Dindyal; Doncel, Gustavo F.; Parang, Keykavous

doi:10.1021/mp300361a

Cited by 36 publications

(54 citation statements)

References 28 publications

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“…The pTyr-Glu-Glu-Ile (GpYEEI) peptide template has been reported to be an optimal binding sequence for the Src SH2 domain of Src kinase. 25 The cellular uptake of F′-GpYEEI was monitored in the presence of P-AuNPs in SK-OV-3 cells. FACS analysis showed that the cellular uptake of F′-GpYEEI was enhanced 3.5- and 12.8-fold by l(KW) 5 -AuNPs and c[KW] 5 -AuNPs, respectively (Figure 10), suggesting that these systems may function as a delivery tools for F′-GpYEEI.…”

Section: Resultsmentioning

confidence: 99%

Surface Decorated Gold Nanoparticles by Linear and Cyclic Peptides as Molecular Transporters

Shirazi

Tiwari

et al. 2013

Mol. Pharmaceutics

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Gold nanoparticles (AuNPs) were synthesized in situ in a green and rapid method from the reaction of reducing linear and cyclic peptides containing tryptophan and lysine residues, (KW)5 and cyclic [KW]5, with an aqueous solution of HAuCl4 and were evaluated as cellular nanodrug delivery systems. The cyclic or linear nature of the peptide was found to determine the morphology and size of the formed peptide-AuNPs and their in vitro molecular transporting efficiency. While cyclic [KW]5-AuNPs formed sponge-like agglomerates, linear (KW)5-AuNPs demonstrated ball-shaped structures. A comparative flow cytometry study showed that the cellular uptake of fluorescence-labeled anti-HIV drugs (emtricitabine (FTC) and lamivudine (3TC)) in human Leukemia (CCRF-CEM) cells, and a negatively charged cell-impermeable phosphopeptide (GpYEEI) in human ovarian adecarcinoma (SK-OV-3) cells was significantly higher in the presence of cyclic [KW]5-AuNPs than that of linear (KW)5-AuNPs, parent cyclic [KW]5, and linear (KW)5 peptides. For example, the cellular uptake of F′-GpYEEI was enhanced 12.8-fold by c[KW]5-AuNPs. Confocal microscopy revealed the localization of fluorescence-labeled-3TC in the presence of c[KW]5-AuNPs mostly in nucleus in SK-OV-3 cells after 1 h. On the other hand, l(KW)5-AuNPs delivered fluorescence-labeled-3TC in cytoplasm. These data suggest that non-cell penetrating peptides can be converted to efficient molecular transporters through peptide-capped AuNPs formation.

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Section: Resultsmentioning

confidence: 99%

Surface Decorated Gold Nanoparticles by Linear and Cyclic Peptides as Molecular Transporters

Shirazi

Tiwari

et al. 2013

Mol. Pharmaceutics

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“…To monitor the molecular transporter ability of PAs, a carboxyfluorescein derivative of 3TC (F′-3TC) was synthesized as described previously. 20,21 …”

Section: Resultsmentioning

confidence: 99%

Peptide Amphiphile Containing Arginine and Fatty Acyl Chains as Molecular Transporters

Shirazi

Tiwari

et al. 2013

Mol. Pharmaceutics

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Peptide amphiphiles (PAs) are promising tools for the intracellular delivery of numerous drugs. PAs are known to be biodegradable systems. Here, four PA derivatives containing arginine and lysine conjugated with fatty acyl groups with different chain length, namely PA1: R-K(C14)-R, PA2: R-K(C16)-R, PA3: K(C14)-R-K(C14), and PA4: K(C16)-R-K(C16), where C16 = palmitic acid and C14 = myristic acid, were synthesized through Fmoc chemistry. Flow cytometry studies showed that among all synthesized PAs, only K(C16)-R-K(C16), PA4 was able to enhance the cellular uptake of a fluorescence-labeled anti-HIV drug 2′,3′-dideoxy-3′-thiacythidine (F′-3TC, F′ = fluorescein) and a biologically important phosphopeptide (F′-PEpYLGLD) in human leukemia cells (CCRF-CEM) after 2 h incubation. For example, the cellular uptake of F′-3TC and F′-PEpYLGLD was enhanced approximately 7.1- and 12.6-fold in the presence of the PA4 compared to those of the drugs alone. Confocal microscopy of F′-3TC and F′-PEpYLGLD loaded PA4 in live cells showed significantly higher intracellular localization than the drug alone in human ovarian cells (SK-OV-3) after 2 h incubation. The HPLC results showed that loading of Dox by the peptide amphiphile was 56% after 24 h. The loaded Dox was released (34%) within 48 h intracellularly. The CD results exhibited that the secondary structure of the peptide was changed upon interactions with Dox. Mechanistic studies revealed that endocytosis is the major pathway of the internalization. These studies suggest that PAs containing appropriate sequence of amino acids, chain length, charge, and hydrophobicity can be used as cellular delivery tools for transporting drugs and biomolecules.

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“…12,13 Peptidyl polyarginine dodecandicarboxylate resin 12 (0.7 g), the nucleoside analogues ( 1 , 8 , or 9 , 1.1 mmol), HBTU (417 mg, 1.1 mmol), and HOAt (148 mg, 1.1 mmol) were dissolved in anhydrous DMF (25 mL) in a round bottom flask (100 mL) followed by the addition of DIPEA (1.95 mmol, 342 μL) and DIC (2.5 mmol, 383 μL) (Scheme 2). The reaction vessels were flushed with N 2 and placed on a shaker at 4000 rpm to mix the reagents.…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly-L-Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors

Pemmaraju

Malekar

Agarwal

et al. 2014

Nucleosides, Nucleotides and Nucleic Acids

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The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5–16.6 μM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 μM and 3.1 μM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions.

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Emtricitabine Prodrugs with Improved Anti-HIV Activity and Cellular Uptake

Cited by 36 publications

References 28 publications

Surface Decorated Gold Nanoparticles by Linear and Cyclic Peptides as Molecular Transporters

Surface Decorated Gold Nanoparticles by Linear and Cyclic Peptides as Molecular Transporters

Peptide Amphiphile Containing Arginine and Fatty Acyl Chains as Molecular Transporters

Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly-L-Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors

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