Antiviral effectiveness

Nonenzymatic fluorinated amino acids (182) have been developed by enzymatic and chemical methods as bioactive compounds siace the antiviral effect of fluorinated alanine was found (183). 

Ara-A is phosphorylated in mammalian cells to ara-AMP by adenosine kinase and deoxycytidine kinase. Further phosphorylation to the di- and triphosphates, ara-ADP and ara-ATP, also occurs. In HSV-1 infected cells, ara-A also is converted to ara-ATP. Levels of ara-ATP correlate directly with HSV rephcation. It has recently been suggested that ara-A also may exhibit an antiviral effect against adenovims by inhibiting polyadenylation of viral messenger RNA (mRNA), which may then inhibit the proper transport of the viral mRNA from the cell nucleus. 

Fig. 7. Adenosine and guanosine analogues with both RNA and DNA antiviral effectiveness.

Ribavirin is not incorporated into the DNA or RNA of either mammalian or viral systems. It has been shown (123), however, that a high dosage of ribavirin given over a prolonged period to Rhesus monkeys results in anemia of red blood cells. This effect is dose related and reversible upon cessation of treatment. Guanosine partially reverses the antiviral effect of ribavirin against certain vimses. 

Although the stmctures of ribavirin and selenazofutin are similar, they appear to exert their antiviral action at different enzyme sites along the same biochemical pathway. Selenazofutin forms the nicotinamide adenosiae dinucleotide (NAD) analogue, which inhibits IMP dehydrogenase by binding ia place of the NAD cofactor, and hence this potent reduction of guanylate pools is responsible for the antiviral effect of selenazofutin. 

In addition to their direct antiviral properties described earlier, IFNs exhibit potent immunomodulatory properties that contribute to their antiviral effects by activating... 

Polyethylene glycol (PEG) consists of repeating units of ethylene glycol forming linear or branched polymers with different molecular masses. Pegylation is the process by which PEG chains are covalently attached to lEN molecules. Pegylation confers a number of properties on lEN-a molecules, such as sustained blood levels that enhance antiviral effectiveness and reduce adverse reactions, as well as a longer half-life and improved patient compliance (Kozlowski et al. 2001). 

In nonresponders to IFN-a-ribavirin, the antiviral effect of boceprevir appeared to be strictly additive to that of pegylated IFN-a2b (Sarrazin et al. 2007). In an ongoing phase II chnical trial, higher doses of boceprevir are being administered to treatment-naive patients, in combination with pegylated IFN-a and ribavirin. 

Burke DH, Scales L, Andrews K, Gold L (1996) Bent pseudoknots and novel RNA inhibitors of type 1 human immunodeficiency virus (HlV-1) reverse transcriptase. J Mol Biol 264 650-666 Burrer R, Neuman BW, Ting JP, Stein DA, Moulton HM, Iversen PL, Kuhn P, Buchmeier MJ (2007) Antiviral effects of antisense morphoUno oligomers in murine coronavirus infection models, J Virol 81 5637-5648... 

In addition, stndies evaluating interferon alpha/beta and interlenkin-16 expression have shown snbstantial antiviral effects against HlV-1 in vitro and in a humanized mouse model (Cremer et al. 2000 Lanret et al. 1994 Sanhadji et al. 1997 Zhou etal. 1997). 

Li XL, Blackford JA, Hassel BA (1998b) RNase L mediates the antiviral effect of interferon through a selective reduction in viral RNA during encephalomyocarditis virus infection. J Virol 72 2752-2759... 

HCV-796 is a non-nucleosidic NS5B polymerase inhibitor with potent antiviral activity in vitro. A phase lb study was performed to determine the antiviral activity, pharmacokinetics, and safety of HCV-796 in patients with chronic HCV infection. Maximum antiviral effects were achieved after 4 days of treatment with a mean reduction of HCV-RNA of 1.4 loglOIU/ml. Combination of HCV-796 with pegylated interferon-a led to a greater reduction of viral RNA load (3.3-3.5 loglO lU/ml) after a 14 days treatment interval. 

Virus replication comprises numerous biochemieal transformations that might provide suitable targets for antiviral therapy. The antiviral effect of thiosemicarbazones was first demonstrated by Hamre et al. [53, 54], who showed that p-aminobenzaldehyde-3-thiosemicarbazone and several of its derivatives were active against vaccinia virus in mice. These studies were extended to include thiosemicarbazones of isatin, benzene, thiophene, pyridine, and quinoline derivatives, which also showed activity against vaccinia-induced encephalitis. The nature of the aldehyde/ketone moiety was not as significant as the presence of the thiosemicarbazide side chain the latter was deemed essential for antiviral activity. 

Lamivudine (Epivir-HBV) is an oral synthetic cytosine nucleoside analogue having antiviral effects against HIV and hepatitis B virus. In patients with chronic hepatitis B, lamivudine is effective in suppressing hepatitis B viral replication, normalizing... 

Utilizing the same aryl fluoride linker on conventional MeOPEG polymer, these authors also presented a microwave-accelerated liquid-phase synthesis of benzimidazoles (Scheme 7.70) [79]. This bicydic pharmacophore is an important and valuable structural element in medicinal chemistry, showing a broad spectrum of pharmacological activities, such as antihistaminic, antiparasitic, and antiviral effects. 

Figure 8.4 Outline of how the 2 -5 synthetase system promotes its antiviral effect. The 2 —5 phosphodiesterase off switch is omitted for clarity. Refer to text for details...

Figure 8.6 Outline of how the eIF-2a protein kinase system promotes an antiviral effect...

Figure 4. A typical viability curve for HIV-infected cell in the presence of anti-HlVdrug. EC50 is 50% antiviral effective concentration. CC50 is 50% cytotoxic concentration.

Drug therapy is used to suppress viral replication by immune mediating or antiviral effects. Interferon 2b lbN-fb1 lamivudine, telbivudine, ade-fovir entecavir, and pegylated IFN-a2a (PEG-IFN) are approved in the United States for first-line treatment of chronic HBV. 

In several studies on the antiviral effects of NO on HIV-1 infection, the proviral or antiviral effects of NO seem to be strictly related to the active production of NO during HIV-1 infection. The universal speculative interpretation of the dichotomous effect of NO is that overproduction of this substance, especially in the primary infection and in late stages of the disease, leads to active viral replication with consequent harmful effects on the course of the disease. Conversely, low production of NO may cause a reduction in or inhibition of HIV-1 replication, especially during the symptomless stage of the disease, or during treatment with highly active combined antiretroviral drugs. 

AZT works by specifically blocking DNA synthesis carried out by HIV reverse transcriptase. Other related compounds are also being tested to see if they specifically affect HIV reverse transcriptase. Such compounds might have equivalent antiviral effects. If they have fewer side effects than AZT, they may be even more effective in treating HIV-infected individuals. Two additional antivirals related to AZT have recently been approved for anti-HIV therapy, dideoxy-inosine (DDI) and dideoxycytosine (DDC). These drugs are predominantly recommended for individuals who cannot tolerate AZT, or for whom AZT has ceased to be effective although they are effective against HIV, they do have side effects. Nevertheless, they may be important because AZT does not indefinitely reduce the amount of virus in HIV-infected individuals. 

Saint-John s-wort was used in ancient Greece and medieval Europe, where it was believed to ward off evil spirits. Its name derives from wort, the Old English word for herb, and the fact that it was harvested in Europe on the eve of St. John s day (June 24th) and burned to purify the air (Fleiligenstein and Guenther 1998). Traditional uses include treatment of depression, insomnia, enuresis, and anxiety. Modern use has focused on its antidepressant effects and possible antiviral effects for treatment of the human immunodeficiency virus (FIIV) (Fleiligenstein et al. 1998) (table 7.3). There has been some interest in its antiglioma effects as well (Couldwell et al. 1993). 

Romero MR, Serrano MA, Vallejo M, Efferth T, Alvarez M, Marin JJ. (2006) Antiviral effect of artemisinin from Artemisia annua against a model member of the Flaviviridae family, the bovine viral diarrhoea virus (BVDV). Planta Med 72 1169-1174. 

In order to identify novel lead compounds with antiviral effects, methanol and aqueous extracts of some medicinal plants in the Zingiberaceae family were screened for inhibition of proteases from human immunodeficiency virus type 1 (HIV-1), hepatitis C virus (HCV) and human cytomegalovirus (HCMV). By bioassay-guided fractionation, eight fiavones were isolated from the black rhizomes of Kaempferia parviflora Wall, ex Baker. The most effective inhibitors, 5-hydroxy-7-methoxyfiavone and 5,7-dimethoxyflavone, inhibited HIV-1 protease, with an inhibitory concentration 50 (IC50) values of 19 0,M. Moreover, 5-hydroxy-3,7-dimethoxyflavone inhibited HCV protease and HCMV protease, with IC50 values of 190 and 250 pM, respectively. 

Song JM, Lee KH, Seomg BL. (2005) Antiviral effect of catechins in green tea on influenza virus. Antiviral Res 68 66-74. 

Yang C, Chen D. (2008) Biflavanones, flavonoids and coumarins from the roots of Stellera chamaejasme and their antiviral effect on hepatitis B virus. 

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