sea algae extracts as potential antiviral drugs

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Gen Pharmacol. 1997 Oct;29(4):497-511.

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. PMID: 9352294