Multibranched V3 peptides inhibit human immunodeficiency virus infection in human lymphocytes and macrophages

Yahi, Nouara; Fantini, Jacques; Mabrouk, Kamel; Rochat, Hervé; Rietschoten, J. Van; Sabatier, Jean‐Marc

doi:10.1007/978-94-011-1468-4_406

Cited by 8 publications

(38 citation statements)

References 22 publications

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“…After 1 h at 37°C, the plates were washed five times with 200 l of PBS, each well was individualized, and the radioactivity was determined in a ␤ scintillation counter (Beckman, Marseille, France). In some experiments, nonrelevant multibranched peptides (15) Recombinant gp120 ELISA-100 l of anti-gp120 polyclonal sheep antibodies directed to the C-terminal domain of gp120 (10 g/ml in 5 mM Tris-HCl, pH 7.4, 150 mM NaCl) were incubated in Immulon 1 multiwell plates overnight at 4°C. The plates were washed three times with 25 mM Tris-HCl, pH 7.6, 144 mM NaCl and saturated with 5 mM Tris-HCl, pH 7.4, 150 mM NaCl, low fat dry milk 2% (saturation buffer) for 120 min at room temperature.…”

Section: Materials-spc3 Ie (Gpgraf)mentioning

confidence: 99%

“…Cell Culture-Human peripheral blood mononuclear cells (PBMC) were obtained from healthy donors, activated with phytohemagglutinin, and cultured in RPMI 1640 medium containing 10% fetal calf serum and interleukin 2 as described (22). The human T-lymphoblastoid C8166 cell line was grown in RPMI 1640 containing 10% fetal calf serum.…”

Section: Materials-spc3 Ie (Gpgraf)mentioning

confidence: 99%

“…Due to the high variability of the V3 loop sequence, the neutralizing activity of anti-V3 antibodies is generally restricted to one or, in the best cases, to a few related HIV-1 isolates, which renders vaccinal strategies particularly puzzling (10,11). However, since the V3 domain of most HIV-1 strains contains several well conserved basic amino acid residues (12), it can bind to a wide variety of anionic compounds, including sulfated polysaccharides, heparin, and suramin, which are efficient inhibitors of HIV-1 infection in vitro (13)(14)(15). Moreover, the V3 loop is also involved in the recognition of galactosylceramide (GalCer), a glycosphingolipid allowing HIV-1 entry into CD4-negative cells of neural and colonic origin (16 -19).…”

mentioning

confidence: 99%

“…These analogs have been first evaluated for their ability to inhibit the binding of [ 3 H]suramin to SPC3, a synthetic peptide displaying eight V3 consensus motifs (GPGRAF) radially branched on uncharged poly-Lys core matrix (15). This prescreening assay proved useful to select those analogs that recognized the V3 loop, and a good correlation was found between the anti-HIV-1 activity of a given analog and its affinity for the V3 loop.…”

mentioning

confidence: 99%

“…This article must therefore be hereby marked "advertisement" in accordance with 18 synthesized according to Tam (21) purified to homogeneity, and the amino acid analysis of the purified peptide agreed with the deduced amino acid ratios. The other peptides used in this study were obtained as described previously (22). [ 3 H]Suramin (49 Ci/mmol) was purchased from Isotopchim (Ganagobie-Peyruis, France).…”

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confidence: 99%

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Synthetic Soluble Analogs of Galactosylceramide (GalCer) Bind to the V3 Domain of HIV-1 gp120 and Inhibit HIV-1-induced Fusion and Entry

Fantini¹,

Hammache²,

Delézay³

et al. 1997

Journal of Biological Chemistry

119

107

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Galactosylceramide (GalCer) is an alternative receptor allowing human immunodeficiency virus (HIV)-1 entry into CD4-negative cells of neural and colonic origin.Several lines of evidence suggest that this glycosphingolipid recognizes the V3 region of HIV-1 surface envelope glycoprotein gp120. Since the V3 loop plays a key role in the fusion process driven by HIV-1, we decided to synthesize soluble analogs of GalCer with the aim to develop a new class of anti-HIV-1 agents that could neutralize HIV-1 infection through masking of the V3 loop. We describe a short route, in three steps, for the synthesis of soluble analogs of GalCer, using unprotected lactose as the starting sugar. The analogs were prescreened in an assay based on the interaction between a V3 loopderived synthetic peptide and [ 3 H]suramin, a polysulfonyl compound displaying high affinity for the V3 loop. One of the soluble analogs, i.e. CA52(n15), strongly inhibited the binding of [ 3 H]suramin to the V3 peptide, with an IC 50 of 1.2 M. This molecule was also able to inhibit [ 3 H]suramin binding to recombinant gp120 with similar activity. Using a competition enzyme-linked immunosorbent assay with highly specific anti-gp120 monoclonal antibodies, the region recognized by CA52(n15) could be mapped to amino acids 318 -323, which corresponds to the highly conserved consensus motif GPGRAF. Interestingly, the region recognized by suramin, i.e. IQRGP-R-F, was partially overlapping this motif. CA52(n15) was able to inhibit HIV-1-induced cell fusion as well as HIV-1 entry into both CD4 ؉ and CD4 ؊ / GalCer ؉ cells. A structure-activity relationship study showed that: (i) the antiviral activity of soluble analogs of GalCer correlates with V3 loop binding, and (ii) the hydrophobic moiety of the molecule plays an important role in this activity. Taken together, these data show that synthetic analogs of GalCer can inhibit HIV-1 entry into both CD4 ؊ and CD4 ؉ cells through masking of the V3 loop.

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Section: Materials-spc3 Ie (Gpgraf)mentioning

confidence: 99%

Section: Materials-spc3 Ie (Gpgraf)mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Synthetic Soluble Analogs of Galactosylceramide (GalCer) Bind to the V3 Domain of HIV-1 gp120 and Inhibit HIV-1-induced Fusion and Entry

Fantini¹,

Hammache²,

Delézay³

et al. 1997

Journal of Biological Chemistry

119

107

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A Unifying Theory

Fantini¹,

Yahi²

2015

Brain Lipids in Synaptic Function and Neurological Disease

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Synthesis, gp120 binding and anti-HIV activity of fatty acid esters of 1,1-linked disaccharides

Bachan¹,

Fantini²,

Joshi³

et al. 2011

Bioorganic & Medicinal Chemistry

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Inspired by the anti-human immunodeficiency virus (HIV) activity of analogues of β-galactosylceramide (GalCer), a set of mono- and di- saccharide fatty acid esters were designed as GalCer mimetics and their binding to the V3 loop peptide of HIV-1 and anti-HIV activity evaluated. 1,1-linked Gal-Man and Glu-Man disaccharides with an ester on the Man subunit bound the V3 loop peptide and inhibited HIV infectivity in single round infection assays with the TZM-bl cell line. IC50's were in the 50 μM range with no toxicity to the cells at concentrations up to 200 μM. These compounds appear to inhibit virus entry at early steps in viral infection since they were inactive if added post viral entry. Although these compounds were found to bind to the V3 loop peptide of gp120, it is not clear that this interaction is responsible for their anti-HIV activity because the relative binding affinity of closely related analogues did not correlate with their antiviral behavior. The low cytotoxicity of these 1,1-linked disaccharide fatty acid esters, combined with the easy accessibility to structurally diverse analogues make these molecules attractive leads for new topical anti-viral agents.

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Multibranched V3 peptides inhibit human immunodeficiency virus infection in human lymphocytes and macrophages

Cited by 8 publications

References 22 publications

Synthetic Soluble Analogs of Galactosylceramide (GalCer) Bind to the V3 Domain of HIV-1 gp120 and Inhibit HIV-1-induced Fusion and Entry

Synthetic Soluble Analogs of Galactosylceramide (GalCer) Bind to the V3 Domain of HIV-1 gp120 and Inhibit HIV-1-induced Fusion and Entry

A Unifying Theory

Synthesis, gp120 binding and anti-HIV activity of fatty acid esters of 1,1-linked disaccharides

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