Antiviral structural requirements

Cytotoxic activity, like cytostatic and antiviral activity, requires specific structural entities in a molecule4 7-). All these activities may be derived from the same structural moiety, or various parts of the molecule may be responsible for them. Thus, structural modifications in an antitumor compound are extremely useful for... 

A second structural requirement for the interferon-inducing capacity (antiviral activity) of synthetic polynucleotides is a stable, highly ordered secondary, hence double-stranded structure based on complementary base-pairing. The stability of the complex is reflected in its Tm (thermal stability) value. From a comparative study of different double-stranded RNA duplexes, De Clercq and Merigan61-1 and De Clercq et al. 53-) concluded that a Tm value higher than 60 °C (calculated for 0.15M Na+) was needed for full expression of antiviral activity. Since thermal stability represents a valuable measure of the overall stability of double-stranded RNAs116 double-stranded RNAs with Tm values higher than 60 °C may also be considered to be the most stable ones at 37 °C. 

These two compounds may possess some clinical advantage over ara-A due to their low systemic toxicity. The antiviral effects of phosphonoformic acid (PFA, foscarnet sodium), which is presently in Phase III clinical trials in Europe, 3 have been discussed in a recent review.91 The synthesis and structural requirements for antiherpes activity of a series of PFA esters have also been reported.92... 

There have been some interesting probes into the structural requirements for activity with double-stranded polynucleotides. Greater in vitro antiviral activity than is found with poly IC can be obtained by the sequential addition of the single-stranded homopolymer constituents e.g. addition of poly I followed at 10 min or even 1 day by poly C causes enhanced antiviral activity as does the addition of poly C followed at 1 min or 10 min by poly I. vivo the homopolymers must be injected intravenously within 1 minute of each other to achieve interferon levels even comparable with poly IC. This may well be a reflection upon the metabolic stability of single double-stranded RNA. Incubation of poly IC or even the alternating ribonucleotide copolymer poly r (A-U) at 37 in... 

S. Sim, and R. H. Raper. 5-Substituted deoxyuridines - structural requirements for antiviral activity... 

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