Dextran sulfate and other polyanionic anti-HIV compounds specifically interact with the viral gp120 glycoprotein expressed by T-cells persistently infected with HIV-1

doi:10.1016/0042-6822(90)90440-3

Virology

Volume 175, Issue 2, April 1990, Pages 556-561

https://doi.org/10.1016/0042-6822(90)90440-3 Get rights and content

Abstract

Eighty to 100% of persistently HIV-1-infected HUT-78 cells express the viral glycoprotein gp120 as demonstrated with anti-gp120 monoclonal antibody (mAb) and fluorescence-activated cell sorter (FACS) analysis. Several polyanionic anti-HIV compounds, i.e., dextran sulfate, pentosan polysulfate, heparin, aurintricarboxylic acid (ATA), suramin, and Evans blue, which are known to inhibit the adsorption of HIV particles to CD4⁺ cells, prevented the binding of anti-gp120 mAb to the persistently HIV-1 infected HUT-78 cells. This effect was dose-dependent and reversible. Except for ATA, the polyanionic compounds did not interfere with the binding of Leu3a/OKT4A mAB, indicating that they do not directly bind to the CD4 receptor. Thus, the inhibitory effect of dextran sulfate and its congeners on the interaction of the HIV gp120 with the cellular CD4 receptor can be ascribed to a specific binding (“shielding”) of gp120.

References (19)

M. Ito et al.
Antiviral Res.
(1987)
R. Ueno et al.
Lancet
(1987)
M. Baba et al.
Antiviral Res.
(1988)
H. Nakashima et al.
Antiviral Res.
(1989)
J. Balzarini et al.
Biochem. Pharmacol.
(1988)
H. Nakashima et al.
Japan. J. Cancer Res.
(1987)
O. Bagasra et al.
J. Infect. Dis.
(1988)
D. Schols et al.
J. Gen. Virol.
(1989)
M. Baba et al.
J. Acq. Immune Defic. Syndr.
(1989)

There are more references available in the full text version of this article.

Cited by (197)

The anti-parasitic drug suramin potently inhibits formation of seminal amyloid fibrils and their interaction with HIV-1
2019, Journal of Biological Chemistry
Citation Excerpt :
However, the addition of suramin decreased the SEVI-induced or PCNA-induced enhancement of infection in a dose-dependent manner, indicating that suramin abolished the SEVI- and SE-F–mediated enhancement of HIV-1 infection (Fig. 6, D and F). Suramin has anti-HIV activity (18–20). We also assessed the direct inhibition of HIV-1 SF162 and HIV NL4-3 infection by suramin alone, and the IC50 values were 3.17 and 0.21 μm, respectively (Fig. S4).
Seminal amyloid fibrils are made up of naturally occurring peptide fragments and are key targets for the development of combination microbicides or antiviral drugs. Previously, we reported that the polysulfonic compound ADS-J1 is a potential candidate microbicide that not only inhibits HIV-1 entry, but also seminal fibrils. However, the carcinogenic azo moieties in ADS-J1 preclude its clinical application. Here, we screened several ADS-J1–like analogs and found that the antiparasitic drug suramin most potently inhibited seminal amyloid fibrils. Using various biochemical methods, including Congo red staining, CD analysis, transmission EM, viral infection assays, surface plasmon resonance imaging, and molecular dynamics simulations, we investigated suramin's inhibitory effects and its putative mechanism of action. We found that by forming a multivalent interaction, suramin binds to proteolytic peptides and mature fibrils, thereby inhibiting seminal fibril formation and blocking fibril-mediated enhancement of viral infection. Of note, suramin exhibited potent anti-HIV activities, and combining suramin with several antiretroviral drugs produced synergistic effects against HIV-1 in semen. Suramin also displayed a good safety profile for vaginal application. Moreover, suramin inhibited the semen-derived enhancer of viral infection (SEVI)/semen-mediated enhancement of HIV-1 transcytosis through genital epithelial cells and the subsequent infection of target cells. Collectively, suramin has great potential for further development as a combination microbicide to reduce the spread of the AIDS pandemic by targeting both viral and host factors involved in HIV-1 sexual transmission.
Suramin inhibits chikungunya virus replication through multiple mechanisms
2015, Antiviral Research
Citation Excerpt :
It was shown that suramin had anti-reverse transcriptase activity against tumor-inducing viruses (De Clercq, 1979) and it was actually the first documented HIV reverse transcriptase inhibitor that was tested in human patients (Broder et al., 1985), but the compound’s side effects outweighed the clinical benefit due to the required long term treatment (Kaplan et al., 1987). A later study revealed that suramin’s anti-HIV-1 activity in vivo was actually due to its inhibitory effect on the interaction between the viral gp120 and the CD4 receptor (Schols et al., 1990). Suramin has also been shown to block the binding or early steps of infection of several DNA and RNA viruses, like herpes simplex virus type-1 (Aguilar et al., 1999), cytomegalovirus (Baba et al., 1993), human hepatitis B virus (Schulze et al., 2007), hepatitis delta virus (Petcu et al., 1988), hepatitis C virus (Garson et al., 1999), dengue virus (Chen et al., 1997), several bunyaviruses (Crance et al., 1997; Ellenbecker et al., 2014; Iqbal et al., 2000; Jiao et al., 2013), norovirus-like particles (Tamura et al., 2004) and enterovirus 71 (Wang et al., 2014), for which the antiviral activity of suramin was also confirmed in an animal model (Ren et al., 2014).
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes severe and often persistent arthritis. In recent years, millions of people have been infected with this virus for which registered antivirals are still lacking. Using our recently established in vitro assay, we discovered that the approved anti-parasitic drug suramin inhibits CHIKV RNA synthesis (IC₅₀ of ∼5 μM). The compound inhibited replication of various CHIKV isolates in cell culture with an EC₅₀ of ∼80 μM (CC₅₀ > 5 mM) and was also active against Sindbis virus and Semliki Forest virus. In vitro studies hinted that suramin interferes with (re)initiation of RNA synthesis, whereas time-of-addition studies suggested it to also interfere with a post-attachment early step in infection, possibly entry. CHIKV (nsP4) mutants resistant against favipiravir or ribavirin, which target the viral RNA polymerase, did not exhibit cross-resistance to suramin, suggesting a different mode of action. The assessment of the activity of a variety of suramin-related compounds in cell culture and the in vitro assay for RNA synthesis provided more insight into the moieties required for antiviral activity. The antiviral effect of suramin-containing liposomes was also analyzed. Its approved status makes it worthwhile to explore the use of suramin to prevent and/or treat CHIKV infections.
Sulfated modification can enhance antiviral activities of Achyranthes bidentata polysaccharide against porcine reproductive and respiratory syndrome virus (PRRSV) in vitro
2013, International Journal of Biological Macromolecules
Achyranthes bidentata polysaccharide (ABPS) was sulfated using the chlorosulfonic acid-pyridine method. The UV-spectrum of sulfated ABPS (sABPS) was characterized with two different absorbance peaks at 196.3 and 262.8 nm. FT-IR spectrum of sABPS exhibited absorption bands at 1236.5 cm⁻¹ (asymmetrical SO stretching vibration) and 822.8 cm⁻¹ (symmetrical COS vibration related to a COSO₃ group). Anti-PRRSV activities of sABPS were tested on MARC-145 cells by MTT method. The results showed that sABPS exhibited significant antiviral activities at lower concentrations in comparison with the non-modified ABPS treated cells, indicating that sulfated modification could enhance antiviral activities of ABPS. These findings may provide the potential value to develop a new-type drug against PRRSV infection.
In vitro evaluation of the antiviral activity of heparan sulfate mimetic compounds against Enterovirus 71
2012, Virus Research
Citation Excerpt :
However, the antiviral activity of the tested compounds was independent of binding to CD4 as they did not interfere with the binding of monoclonal antibodies to the CD4 antigen receptor on MT-4 cells (Baba et al., 1988a). Later work demonstrated that Hep, PPS and some other HS mimetics prevented the binding of anti-gp120 monoclonal antibody to the persistently HIV-1-infected HUT-78 cells, providing evidence for interaction of HS mimetics with HIV-1 gp120 (Schols et al., 1990). The capacity of Hep to prevent viral attachment was also shown for Dengue virus where Hep showed a potent antiviral activity (with an IC50 of 0.3 μg/mL) by inhibiting binding of recombinant surface glycoprotein of dengue virus-2 to Vero cells, while HS and other HS mimetics failed to display such effect.
Enterovirus 71 (EV71) is the causative agent of hand foot and mouth disease (HFMD) and can also cause fatal neurological complications for which currently there is no vaccine or approved antiviral drug. Despite suggestions that heparan sulfate (HS)-like compounds are effective antivirals against various viruses, no research has been undertaken to examine their effects upon EV71. Therefore, this study aimed to investigate the in vitro anti-EV71 effect of HS mimetics (heparin, heparan sulfate, and pentosan polysulfate). The results revealed that all of the compounds exhibited significant antiviral actions (p < 0.05) against EV71 at concentrations less than 250 μg/mL, compared to virus control and positive control, ribavirin. Among the compounds, heparin exhibited the most potent antiviral activity, as 7.81 μg/mL of it prevented the infection by more than 90% (p < 0.05). Assays to reveal the mode of action revealed that all of the compounds were capable of exerting antiviral activity through hindrance of viral attachment to the cells. In addition, some of the compounds could inhibit viral replication when added to cells 1 h before infection, but none significantly reduced viral penetration. Overall, this research revealed that HS mimetic compounds could inhibit EV71 infection, and that HS may be involved in EV71–host cell interactions, as the virus binding to the host cells was significantly hindered by the HS-like compounds but not by ribavirin. Thus, further investigations to discover the molecular mechanisms underlying the anti-EV71 action of HS-like compounds are warranted.
A mammalian two-hybrid system-based assay for small-molecular HIV fusion inhibitors targeting gp41
2011, Antiviral Research
Citation Excerpt :
As shown in Table 1, except for the E. coli polysaccharides, heparin, three fucoidans and hyaluronan showed significant inhibitory activity not only against the luciferase of cotransfection of pG5-SV40-Luc with both two expression plasmids pVP16-NHR and pGAL4-CHR, but also against that of cotransfection with only one the expression plasmid pVP16-NHR or pGAL4-CHR, indicating the inhibition by these polyanions is not due to the interruption of gp41 NHR–CHR interaction, but the sulfate group and glucuronic acid interfering the assay. It has been reported that sulfated polysaccharides can interact with various proteins, such as HIV-1 gp120 glycoprotein (Baba et al., 1988, 1990; Batinić and Robey, 1992; Esté et al., 1997; Schols et al., 1990), HIV-1 tat protein (Hui et al., 2006; Urbinati et al., 2004; Watson et al., 1999), CD4 molecules of cell surface (Lederman et al., 1989; Meiyu et al., 2003), stromal cell-derived factor-1 (Fermas et al., 2008), leucocyte function associated antigen-1 (Vermot-Desroches et al., 1991), through a sulfate (or sulfonate)-mediated interaction. In present study, three fucoidans with different sulfate contents showed different extent of non-specific inhibition, suggesting that the degree of sulfation as well as specific positioning of sulfate group may be the major impact on the cell-based assay, which may also be the reason for that no non-specific inhibition was observed in ADS-J1 and XTT formazan.
gp41 is a major component of the envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) responsible for fusion of the viral envelope with the target cellular membrane. The formation of the trimer-of-hairpins core structure of gp41, via the interaction between its N-terminal heptad repeat (NHR) and its C-terminal heptad repeat (CHR) plays a key role in the membrane fusion process. Hence, inhibitors of trimer-of-hairpins formation have become a promising new class of HIV therapeutics. In the present study, based on the mammalian two-hybrid system, we developed a cell-based assay for detecting small-molecular HIV-1 fusion inhibitors targeting gp41. The optimized assay can be adapted to high-throughput screening in 96- and 384-well microplates with high signal-to-background ratios and acceptable Z′ factors. The known small-molecular gp41 inhibitors, ADS-J1, XTT formazan and tannin acid, tested positive in this assay, with half-maximal inhibitory concentration (IC₅₀) values of 4.9 μM, 5.6 μM and 0.8 μM, respectively. These data suggested that this novel assay is robust, sensitive and specific for identifying small-molecular HIV-1 gp41 inhibitors.
Functionalized Fullerene for Inhibition of SARS-CoV-2 Variants
2023, Small

View all citing articles on Scopus

View full text

Short communicationDextran sulfate and other polyanionic anti-HIV compounds specifically interact with the viral gp120 glycoprotein expressed by T-cells persistently infected with HIV-1

Abstract

Antiviral Res.

Lancet

Antiviral Res.

Antiviral Res.

Biochem. Pharmacol.

Japan. J. Cancer Res.

J. Infect. Dis.

J. Gen. Virol.

J. Acq. Immune Defic. Syndr.

Short communication
Dextran sulfate and other polyanionic anti-HIV compounds specifically interact with the viral gp120 glycoprotein expressed by T-cells persistently infected with HIV-1