Anti-viral activity

Many polysaccharides of eukaryotic origin show non-specific anti-viral activity and this property may be shared by some of the exopolysaccharides. The structural requirements for activity are not immediately evident as the polysaccharides exhibiting this activity are very diverse. 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Hwang DR et al (2006) Synthesis and anti-viral activity of a series of sesquiterpene lactones and analogues in the subgenomic HCV replicon system. Bioorg Med Chem 14(1) 83—91... 

Anti-viral activity via receptor different to type-1 IFN... 

The tubingensins A (379) and B (380) showed activity against the widespread crop pest Heliothis zea, and display in vitro anti-viral activity against herpes simplex virus type 1 with IC50 values of 8 and 9 pg/mL, respectively (346) (see Scheme 2.100). Some bis-basic ethers of carbazoles are anti-viral. When tested against Encephala myocarditis viral infection, several N-ethyl substituted bis-basic carbazoles of the general formula 490 were shown to be active (448) (Scheme 4.9). 

Flavonoids are 15-carbon polyphenols produced by all vascular plants. Well over 4000 distinct flavonoids have now been identified, a limited number of which display therapeutic activity. These substances are generally degraded if taken orally, and are administered medically via the intravenous route. This is probably just as well (the average Western daily diet contains approximately 1 g of flavonoids). A number of flavonoids appear to display anti-viral activity and, hence, are of pharmaceutical interest (Figure 1.12). 

Figure 1.12. Some flavonoids, xanthines and terpenoids. Chrysoplenol B and axillarin are two flavonoids exhibiting anti-viral activity against Rhinovirus (causative agent of the common cold). Examples of xanthines include caffeine and theophylline. Terpenes are polymers of the 5-carbon compound isoprene. Perhaps the best-known such substance discovered in recent years is the diterpenoid taxol, which is used as an anti-tumour agent...

Interferons induce a wide range of biological effects. Generally, type I IFNs induce similar effects, which are distinct from the effects induced by IFN-y. The most pronounced effect of type I IFNs relates to their anti-viral activity, as well as their anti-proliferative effect on various cell types, including certain tumour cell types. Anti-tumour effects are likely due not only to a direct anti-proliferative effect on the tumour cells themselves but also due to the ability of type I IFNs to increase natural killer (NK) cell and T cytotoxic cell activity. These cells can recognize and destroy cancer cells. 

The molecular basis by which IFNs promote their characteristic effects, particularly anti-viral activity, is understood at least in part. IFN stimulation of the JAK-STAT pathway induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral replication. These anti-viral gene products are generally enzymes, the most important of which are 2 -5 oligoadenylate synthetase (2, 5-An synthetase) and the eIF-2a protein kinase. 

Interferon gamma is an activator of macrophages. Its anti-viral activity is limited compared to that of interferon alfa. Human recombinant interferon gamma restores, at least in part, macrophage cytotoxicity and with that decreases the incidence of infections in patients with chronic granulomatous diseases. Its adverse effects consist mainly of flu-like syndrome skin rashes may occur. 

As an example ddl (2,3-dideoxyinosine), an inhibitor of the HIV reverse transcriptase (RT-HIV), has an only 30-s half-life at pH 1 (at 37°C). Some formulations allow circumventing the problem of the consequent inefficient oral administration. A chemical alternative consists in the introduction of a fluorine atom in 2j] to disfavour the generation of the oxonium ion involved in the proteolysis (Fig. 16) [57,58], Indeed, the fluorinated analogue is stable in acidic medium while keeping the in vitro anti-viral activity. However, it seems that other problems prevented the clinical development [5,57]. 

Elvucitabine is in phase III development for therapies of HIV and HBV infections. Its anti-viral activity has been shown to result from inhibition of the HIV reverse transcriptase and HBV DNA polymerase (Fig. 35) [99]. 

Mother s milk is an often coined term for products that mimic the natural mother s milk contents. Actual human mother s milk contains about 40-50% casein and 50-60% whey, and about 17% lactoferrin with no beta-lactoglobulin. As I said earlier, mother s milk contains alfa lactoglobulin. This is very different from cow s milk which contains about 80% casein and 20% whey with 1% lactoferrin being average. Lactoferrin has anti-viral activity, and is a potent immune system booster. Obviously this is an advantage for new born human (rug rats) since they lack complete immune system functions. Remember the fact that human mother s milk dominant protein fraction is alfa-lactalbumin Well, there is a research project on going which claims acid folded alfa-... 

Interferons, IFN s belong to a group of cytokines of Mr in the range of 15.000 to 30.000. There are three types of interferons, INF-a, INF-/3 and INF-y. They are released by cells on exposure to inducing agents, such as viruses. A special property of the INF s is their anti-viral activity. 

Nectrisine (an inhibitor of both a-glucosidases and a-mannosidases) has also been reported to have anti-viral activity. It has been shown to inhibit the retrovims Friend leukaemia vims in vivo in mice and it too can potentiate the activity of AZT. ... 

These compounds have functional groups that can modify zinc fingers in NC protein and have anti-viral activity but are not necessarily specific for the virus. In order to initiate studies leading to the design of reagents with greater specificity for the viral NC protein it is necessary to determine the mechanism of action for model compounds and in particular to determine the initial site of attack on the NC protein. 

In 1986, venustatriol (2) was isolated from the red algae Laurencia venusta [5]. This compound was shown to possess many of the same structural features as thyrsiferol (1), with the exception of the stereocenters at Cig and C19 as indicated in Fig. (1). At the time of its isolation, venustatriol (2) was reported to display anti-viral activity against vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1). The absolute configuration of venustatriol (2) was verified by x-ray crystallography, an experiment that facilitated the assignment of the absolute stereochemistry of thyrsiferol (1). 

The diprenylated bibenzyl glepidotin D (162) with one substitution at 3-0 was isolated from the leaves of Glycyrrhiza lepidota is responsible for the anti-viral activity [98], Phytochemical investigation of the liverwort Lethocolea glossophylla yielded four new prenylated bibenzyls (163-166) [99], and a lipid extract of the leaves of Sicilian Glycyrrhiza glabra... 

The anti-virus activity research concerning stilbenoids mainly focuses on HIV. Glepidotin D (162) was isolated from the leaves of Glycyrrhiza lepidota as the compound responsible for the anti-viral activity with an EC50 of 2.0 g/ml and an ICso of 5.0 //g/ml, which excludes the need for further study [98]. 

Nectrisine also has anti-viral activity and inhibits the retrovirus Friend leukaemia virus in vivo in mice and can potentiate the activity of AZT (zidovudine) [103]. Synergistic activity has also been shown when castanospermine and AZT are used in combination therapy in vitro [104], In vivo combination studies with V-butyl-deoxynojirimycin and AZT in human patients mdicated anti-viral activity but caused diarrhoea, abdominal pain and weight loss [103], Chemical modification of V-butyl-deoxynojirimycin to make it better tolerated was suggested. 

Syntheses of oxetanocin A (a nucleoside with anti-viral activity) and related unusual nucleosides with / .v(hydroxymethyl)-branched sugars 02S1. 

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