Polyanions are known to exhibit potent antiviral activity in vitro, and may represent future therapeutic agents. This review summarizes literature reports, pertinent to anionic polymers as antiviral agents. The in vitro antiviral effects of numerous polyanionic compounds (sulphated polysaccharides, negatively charged serum albumin and milk proteins, synthetic sulphated polymers, polymerized anionic surfactants and polyphosphates) are described. This class of antiviral agent exhibits several unique properties that are not shared by other presently known antiviral agents: (i) a remarkable broad-spectrum antiviral activity against HIV-1, HIV-2 and a series of other enveloped viruses; (ii) the ability to inhibit syncytium formation between HIV-infected and normal CD4 T lymphocytes, a mechanism that drastically enhances HIV infectivity; and (iii) a low induction of viral drug-resistance. There is increasing evidence that polyanions interfere with the fusion process, a vital step in the viral replication cycle. The inhibition of virus-cell fusion appears to be the source of the antiviral activity of polyanions. In vivo, the pharmacological properties of polyanions result in a low bioavailability of the drugs to their viral targets, and hence a poor antiviral activity in vivo. It is suggested that polyanions must be used in combination with drug delivery systems in order to become therapeutically useful antiviral agents. Some drug delivery systems are briefly discussed.

SynopsisThe primary hydration process of native biopolymers is analyzed in a brief review of the literature, pertaining to various aspects of biopolymer-water systems. Based on this analysis, a hydration model is proposed that implies that the solution conformation of native biopolymers is stable at and above a critical degree of hydration (hp, = 0.060.1 g HzO/g polymer). This water content corresponds to the fraction of strongly bound water, and amounts to -20% of the primary hydration sphere. In order to test this model, detailed sorption-desorption scanning experiments were performed on a globular protein (a-chymotrypsin). The results obtained are consistent with the proposed hydration model. They show that under certain experimental conditions, sorption isotherms can be obtained that do not exhibit hysteresis. These data represent equilibrium conditions and are thus accessible to thermodynamic treatment. Valid thermodynamic functions, pertinent to the interaction of water with biopolymers in their solution state, can be obtained from these sorption experiments.

Influenza is worldwide one of the deadliest infectious diseases. Lethal influenza mutants can unpredictably arise, as in the 1918 pandemic, or in the 1997 Hong Kong influenza outbreak. Vaccines are today the only protective prophylactic agents, and development of potent new anti-influenza drugs of therapeutic effectiveness appears urgent. It is the aim of the present review, to summarize and discuss the different investigational approaches to this goal. In Medline- and several internet virology database-searches, numerous citations were compiled, and selected according to their relevance to the different topics discussed. The antiviral agents are classified according to their target in the viral replication cycle: proteolytic activation of haemagglutinin, attachment of the virus to specific cell-surface receptors, endocytosis and fusion with the endosomal membrane, uncoating of the nucleocapsid, multiplication, i.e. synthesis of viral RNA and mRNA, and release of the new virus generation from the host cell surface. Potential drugs, directed towards each of these replication steps are described with respect to their mechanism of action, antiviral activity, toxic side effects and induction of resistance. The most promising candidates for safe and potent new influenza drugs, are antiviral agents, directed towards a virus-specific, well conserved target, such as inhibitors of virus-cell fusion, inhibitors of RNA transcriptase and endonuclease, and inhibitors of neuraminidase. It can be hoped that in the near future potent and therapeutically effective anti-influenza drugs will be available.

The effect of dextran sulfate on the fusion of a series of enveloped viruses, bearing specifically different fusion proteins, was investigated. The fusion with model- and with biological membranes was monitored by an R18 fluorescence-dequenching fusion assay. Dextran sulfate strongly suppresses the fusion of orthomxyo- (influenza A (H1N1 and H3N2 subtypes) and influenza B), of toga- (Semliki Forest virus), and of rhabdoviruses (vesicular stomatitis and rabies virus). The fusion of the paramyxo-viruses Sendai and mumps was not significantly affected by the anionic polysaccharide. The response to dextran sulfate was virus-specific, and identical for the different members of one virusfamily, bearing the same fusion protein. It was shown that dextran sulfate attaches with high affinity to the viruses studied, but not to erythrocytes. The anionic polymer appears to attach to the fusion epitope of the viral membrane. The inhibition of virus replication in vitro shows a remarkable correlation with the observed anti-fusion effects of dextran sulfate.

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