Experientia 1989 Oct 15;45(10):996-8 Related Articles, Books, LinkOut


Further characterization of sulfated homopolysaccharides as anti-HIV agents.

Sugawara I, Itoh W, Kimura S, Mori S, Shimada K.

Department of Pathology, University of Tokyo, Japan.

Fucoidan and dextran sulfate showed anti-HIV activities against mononuclear
cells from AIDS patients, and they abrogated HIV reverse transcriptase (RT)
activity by interacting with the HIV envelope in the membranes of target cells.
Furthermore, they showed a synergistic effect with azidothymidine (AZT).

PMID: 2478388 [PubMed - indexed for MEDLINE




Phytomedicine 1999 Nov;6(5):335-40 Related Articles, Books, LinkOut


Antiviral properties of fucoidan fractions from Leathesia difformis.

Feldman SC, Reynaldi S, Stortz CA, Cerezo AS, Damont EB.

Departamento de Quimica Organica-CIHIDECAR, Facultad de Ciencias Exactas y
Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Argentina.

Three fractions of fucoidans isolated from the brown seaweed Leathesia difformis
(Ee, Ec and Ea) were found to be selective antiviral agents against herpes
simplex virus (HSV) types 1 and 2 and human cytomegalovirus. Fraction Ea was the
most active, with IC50 values in the range 0.5-1.9 microg/ml without affecting
cell viability at concentrations up to 400 microg/ml. The antiherpetic activity
of Ea was assessed by three different methods, plaque reduction, inhibition of
virus yield and prevention of HSV-2 induced shut-off of cell protein synthesis,
demonstrating that the inhibitory effect was independent of the antiviral assay
and the multiplicity of infection. The mode of action of Ea could be ascribed to
an inhibitory action on virus adsorption. The fucoidans did not inhibit the
blood coagulation process even at concentrations exceeding more than 100 times
the IC50 value.

PMID: 11962540 [PubMed - indexed for MEDLINE]




Gen Pharmacol 1997 Oct;29(4):497-511 Related Articles, Books, LinkOut


Sulfated polysaccharides extracted from sea algae as potential antiviral drugs.

Witvrouw M, De Clercq E.

Rega institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

The inhibitory effects of polyanionic substances on the replication of herpes
simplex virus (HSV) and other viruses were reported almost four decades ago.
However, these observations did not generate much interest, because the
antiviral action of the compounds was considered to be largely nonspecific.
Shortly after the identification of human immunodeficiency virus (HIV) as the
causative agent of the acquired immune deficiency syndrome (AIDS) in 1984,
heparin and other sulfated polysaccharides were found to be potent and selective
inhibitors of HIV-1 replication in cell culture. Since 1988, the activity
spectrum of the sulfated polysaccharides has been shown to extend to various
enveloped viruses, including viruses that emerge as opportunistic pathogens
(e.g., herpes simplex virus [HSV] and cytomegalovirus [CMV]) in immunosuppressed
(e.g., AIDS) patients. As potential anti-HIV drug candidates, sulfated
polysaccharides offer a number of promising features. They are able to block HIV
replication in cell culture at concentrations as low as 0.1 to 0.01 microgram
ml-1 without toxicity to the host cells at concentrations up to 2.5 mg ml-1. We
noted that some polysulfates show a differential inhibitory activity against
different HIV strains, suggesting that marked differences exist in the target
molecules with which polysulfates interact. They not only inhibit the cytopathic
effect of HIV, but also prevent HIV-induced syncytium (giant cell) formation.
Furthermore, experiments carried out with dextran sulfate samples of increasing
molecular weight and with sulfated cyclodextrins of different degrees of
sulfation have shown that antiviral activity increases with increasing molecular
weight and degree of sulfation. A sugar backbone is not strictly needed for the
anti-HIV activity of polysulfates because sulfated polymers composed of a
carbon-carbon backbone have also proved to be highly efficient anti-HIV agents
in vitro. Other, yet to be defined, structural features may also play an
important role. Sulfated polysaccharides may act synergistically with other
anti-HIV drugs (e.g., azidothymidine [AZT]). They are known to lead very slowly
to virus-drug resistance development and they show activity against HIV mutants
that have become resistant to reverse transcriptase inhibitors, such as AZT,
tetrahydro-imidazo [4,5,l-jk] [1,4]-benzodiazepin-2(1H)-thione (TIBO) and
others. From studies on their mechanism of action we concluded that polysulfates
exert their anti-HIV activity by shielding off the positively charged sites in
the V3 loop of the viral envelope glycoprotein (gp120). The V3 loop is necessary
for virus attachment to cell surface heparan sulfate, a primary binding site,
before more specific binding occurs to the CD4 receptor of CD4+ cells. This
general mechanism also explains the broad antiviral activity of polysulfates
against enveloped viruses. Variations in the viral envelope glycoprotein region
may result in differences in the susceptibility of different enveloped viruses
to compounds that interact with their envelope glycoproteins. The efficacy of
polysulfates in the therapy and/or prophylaxis of retroviral infections and
opportunistic infections remains to be demonstrated both in animal models and
humans. It is important to consider not only treatment of patients who are
already infected with HIV, but also prophylaxis and protection from HIV and/or
other virus infections. Because (i) sexual transmission is responsible for the
large majority of HIV infections worldwide; (ii) this transmission is mostly
mediated via mononuclear cells that infect epithelial cells of the genital
tract; and because (iii) polysulfates effectively inhibit cell-cell adhesion,
polysulfates may be considered as potentially effective in a vaginal formulation
to protect against HIV infection.

Publication Types:
Review
Review, Tutorial

PMID: 9352294 [PubMed - indexed for MEDLINE]




Biomed Pharmacother 1996;50(5):207-15 Related Articles, Books, LinkOut


Chemotherapy of human immunodeficiency virus (HIV) infection: anti-HIV agents
targeted at early stages in the virus replicative cycle.

De Clercq E.

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

Several compounds have been identified that inhibit an early stage in the
replicative cycle of the human immunodeficiency virus (HIV): i) virus
adsorption: polysulfates, polysulfonates, polycarboxylates, polyphosphates, and
polyoxometalates; or ii) virus-cell fusion: plant lectins, negatively charged
albumins and betulinic acid derivatives; iii) virus fusion/uncoating: bicyclam
derivatives; iv) reverse transcription: dideoxynucleoside analogues, acyclic
nucleoside phosphonates and non-nucleoside reverse transcriptase inhibitors. In
principle, HIV may develop resistance to any of these specific anti-HIV agents.
However, virus breakthrough can be completely prevented if these agents, alone
or in combination, are added to the HIV-infected cells from the beginning at
sufficiently high ('knock-out') concentrations.

Publication Types:
Review
Review, Tutorial

PMID: 8949401 [PubMed - indexed for MEDLINE