The use of hairpin DNA duplexes as HIV-1 fusion inhibitors: Synthesis, characterization, and activity evaluation

Xu, Liang; Jiang, Xifeng; Xu, Xiaoyu; Zheng, Borui; Chen, Xueliang; Zhang, Tao; Gao, Fang; Cai, Lifeng; Cheng, Maosheng; Liu, Keliang

doi:10.1016/j.ejmech.2014.05.068

Cited by 6 publications

(10 citation statements)

References 23 publications

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“…T1 contained three hydrophobic groups (one TBDPS and two DMTs) at each end of the helix. The IC 50 for T1 was 1.8 -0.7 mM, comparable to the previously reported IC 50 values of duplex and quadruplex inhibitors [3][4][5][6][7][8][9][10][11][12][13][14][15]. T2 had no hydrophobic group modifications and did not show the anti-HIV-1 fusion activity.…”

Section: Odns and Triplexessupporting

confidence: 66%

“…Single-stranded ODNs showed no or lower activity compared to T1 and T3 ( Table 1), indicating that the formation of a rigid helix structure was conducive to the inhibition of cell fusion. However, the fact that S1, S2, and S4 showed some inhibitory activity is in contrast to the results of DNA duplex-and quadruplex-based inhibitors, whose single ODNs with hydrophobic groups do not show inhibitory activity [14,15]. This discrepancy might be attributable to the longer chains of S1, S2, and S4 (32, 32, and 24 bases, respectively).…”

Section: Odns and Triplexescontrasting

confidence: 47%

“…The cell-cell fusion assay was performed as described [14,15]. HIV-1 envelope glycoprotein (Env)-mediated cellcell fusion was used to determine the inhibitory activity of ODNs in HL2/3 and TZM-bl cells [gifts from the AIDS Reference and Reagent Program, NIH, from Drs.…”

Section: Cell-cell Fusion Assaymentioning

confidence: 99%

“…The FRET assay was carried out as previously described [14,15,21]. The peptide receptor env2.0 containing the primary pocket of the HIV-1 gp41 NHR was mixed with the fluorescence peptide probe CP2-LY, which specifically binds to the pocket.…”

Section: Fret Assaymentioning

confidence: 99%

“…Among these inhibitors, the most representative structure is Hotoda's sequence, d(TGGGAG), which interacts with the V3 loop or CD4-binding site of viral glycoprotein 120 (gp120) [3][4][5][6][7][8][9][10][11][12][13]. Recently, we designed a novel class of DNA duplex-based HIV-1 fusion inhibitors, which have hydrophobic groups at several selected positions [14,15]. A fluorescent resonance energy transfer (FRET)-based inhibitory assay showed that these duplex inhibitors interact with the primary pocket at the glycoprotein 41 (gp41) N-terminal heptad repeat (NHR).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

DNA Triplex-Based Complexes Display Anti-HIV-1-Cell Fusion Activity

Xu¹,

Zhang²,

Xu³

et al. 2015

Nucleic Acid Therapeutics

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Section: Odns and Triplexessupporting

confidence: 66%

Section: Odns and Triplexescontrasting

confidence: 47%

Section: Cell-cell Fusion Assaymentioning

confidence: 99%

Section: Fret Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

DNA Triplex-Based Complexes Display Anti-HIV-1-Cell Fusion Activity

Xu¹,

Zhang²,

Xu³

et al. 2015

Nucleic Acid Therapeutics

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Synthesis, biophysical characterization, and anti-HIV-1 fusion activity of DNA helix-based inhibitors with a p-benzyloxyphenyl substituent at the 5′-nucleobase site

Tang¹,

Han²,

Guo

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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Enfuvirtide−PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties

Cheng

Wang

Zhang

et al. 2016

European Journal of Medicinal Chemistry

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Enfuvirtide (ENF) is a clinically used peptide drug for the treatment of HIV infections, but its poor pharmacokinetic profile (T1/2 = 1.5 h in rats) and low aqueous solubility make the therapy expensive and inconvenience. In this study, we present a simple and practical strategy to address these problems by conjugating ENF with polyethylene glycol (PEG). Site-specific attachment of a 2 kDa PEG at the N-terminus of ENF resulted in an ENF-PEG (EP) conjugate with high solubility (≥3 mg/mL) and long half-life in rats (T1/2 = 16.1 h). This conjugate showed similar antiviral activity to ENF against various primary HIV-1 isolates (EC50 = 6-91 nM). Mechanistic studies suggested the sources of the antiviral potency. The conjugate bound to a functional domain of the HIV gp41 protein in a helical conformation with high affinity (Kd = 307 nM), thereby inhibiting the gp41-mediated fusion of viral and host-cell membranes. As PEG conjugation has advanced many bioactive proteins and peptides into clinical applications, the EP conjugate described here represents a potential new treatment for HIV infections that may address the unmet medical needs associated with the current ENF therapy.

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The use of hairpin DNA duplexes as HIV-1 fusion inhibitors: Synthesis, characterization, and activity evaluation

Cited by 6 publications

References 23 publications

DNA Triplex-Based Complexes Display Anti-HIV-1-Cell Fusion Activity

DNA Triplex-Based Complexes Display Anti-HIV-1-Cell Fusion Activity

Synthesis, biophysical characterization, and anti-HIV-1 fusion activity of DNA helix-based inhibitors with a p-benzyloxyphenyl substituent at the 5′-nucleobase site

Enfuvirtide−PEG conjugate: A potent HIV fusion inhibitor with improved pharmacokinetic properties

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