Antiviral inhibition

Tang C, LoeUger E, Kinde I et al. (2003) Antiviral inhibition of the HIV-1 capsid protein. J Mol Biol 327 1013-1020... 

Lamivudine (Epivir, Epivir- Antiviral Inhibits HIV reverse transcriptase and DNA polymerase... 

Antiviral, inhibits HIV replication in phase I/II clinical trials. 

C. trichotomum Hypertension Isomartynoside Antiviral Inhibition of HIV-1 integrase Inactive [98]... 

Acyclovir Antiviral inhibits DNA synthesis in herpes simplex (HSV) and variceUa-... 

S-2-propenylcysteine thiosulfinate (allicin) antibacterial, antifungal, antiprotozoal, antiparasitic, antiviral, inhibition of RNA synthesis, inhibition of cholesterol biosynthesis, iron oxidation in hemoglobin. 12, 85. 87-89, 91.112-113... 

Plants and microorganisms produce unique and diverse chemical stmctures, some of which act as immunomodulators (18—28). Of specimens used in traditional medicine, approximately 450 plant species have shown antiviral activity out of 4000 plants screened (19). Several tannins (20) exhibit strong inhibition of tumor promotion experimentally. Pretreatment of mice with small amounts of tannins for several days strongly rejected transplanted tumors. This activity has been claimed to be effected through enhancement of host-mediated antitumor activity. 

Interferons (lENs) (52,53), a family of species-specific vertebrate proteins, confer nonspecific resistance to a broad range of viral infections, affect cell proliferation, and modulate immune responses. AH three principal interferons, a-interferon (lEN-a) produced by blood leucocytes, P-interferon (lEN-P) by fibroblasts, and y-interferon (lEN-y) by lymphocytes, also have antiviral activity. The abiUty of interferons to inhibit growth of transplantable and carcinogen-induced tumor led to research showing the direct antiproliferative and indirect immune-mediated antitumor activities (see Chemotherapeutics, anticancer). IENs have been found to be efficacious in certain malignancies and viral infections, eg, hairy cell leukemia (85% response) and basal cell carcinoma (86% response). However, the interferons do have adverse side effects (54). 

The streptovaricins inhibit the reverse transcriptase of some RNA oncogenic vimses that may be involved in the process of viral transformation (see Antiviral agents). The atropisostreptovaricins again have similar activities to the corresponding natural isomers. The streptovals and streptovarone exhibit gready improved activity against reverse transcriptase relative to the streptovaricins (85), but their in vitro activities were low (86). The damavaricins also inhibit reverse transcriptase (4) as well as tumor cell growth (87). 

The antiviral activity of the ansamacroHdes does not result from inhibition of RNA polymerase but rather from the inhibition of the assembly of the vims particles (141,258). 

I eplanocins. Neplanocins A—D and E (37—41) are carbocycHc nucleoside antibiotic products oi Ampullariella regularis (1,4) that are stmcturaHy related to (36) in that they contain either a cyclopentene or epoxy cyclopentane ring (121,122). The chemical syntheses of (37—41) and the 3-deazaneplanocins have been reported (123—126). Compound (37), which is converted to its 5 -triphosphate, has potent antitumor and antiviral activities (127—129). It strongly inhibits SAM in ceUs and vimses (128—131) and is converted to the 3 -keto derivative by A-adenosyUiomocysteine hydrolase (132,133). 

Thiosemicarba2ones have long been used as antiviral agents, principally against pox vimses of the vaccinia family. One compound of this series, the isatin derivative (6) C HgN OS, has been used prophylacticaHy to prevent outbreaks of smallpox in humans (10) and to inhibit the protein synthesis in poxvims-infected cells. The molecular mechanics relating to this property are still not known (11), though the binding of a metal ion may be a key factor... 

Replacement of the sulfur atom in the thiosemicarba2one moiety by an oxygen atom leads to a loss of antiviral activity. Methisa2one has no significant effect on vaccinia vims DNA synthesis (14) but seems to inhibit late protein synthesis by a mechanism that remains to be elucidated. 

Amino-5-iodo-2, 5 -dideoxyuridine [56045-73-9] (13) C2H22IN2O4, was synthesized ia 1975 (27) and was found effective against herpes keratitis ia rabbits (28). This compound is markedly less cytotoxic than IdU, iadicating that it may have a safer and more specific mode of antiviral activity. A potential limitation of this group of nucleosides is their specificity, for they fail to inhibit all strains of herpes vimses. The specific antiviral activity of (13) is considered to be a result of the incorporation of the 5 -Ai-phosphate into both viral and host DNA in infected cells, but not into the DNA of normal cells. Phosphorylation of (13) occurs only in herpes vims-infected cells, brought about by a vims-induced thymidine kinase (29). 

The 3, 5 -cyclic phosphate of ara-C has shown significant antiviral activity in vivo with an efficacy greater than that exhibited by ara-C itself (35). It was speculated that the 3, 5 -cycHc phosphate moiety may inhibit the deamination of ara-C, thus causiag the iacreased in vivo potency. A number of derivatives of ara-C have been prepared ia an effort to improve on antiviral activity and to reduce the toxicity. One such derivative is 2 - uoro-5-iodo-l-p-D-arabiQofuranosylcytosiae [69123-90-6] (FIAC, 17), synthesized (36) ia 1979. It is active against certain DNA vimses. FIAC,... 

Purine Nucleoside Derivatives. A number of purine nucleoside analogues are also found to be active against several DNA vimses (Fig. 3). The clinically active antiviral drug ara-A (9-P-D-arabinofuranosyladenine [5536-17-4] vidarabine, 23) is active against a number of DNA vimses in vivo and also inhibits certain RNA tumor vimses which repHcate through a DNA intermediate (43). Ara-A, was first synthesized in 1960 (44) and later... 

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. 

It is likely that ara-HxMP similarly exerts its antiviral activity in the form of the triphosphate, ara-HxTP, since ara-HxTP inhibits HSV-1 DNA polymerase (49). Another possible explanation of the antiviral activity of ara-HxTP is that it is metaboHcaHy converted to ara-AMP. In fact, it has been shown at Wellcome Research Laboratories that ara-HxMP is a substrate for adenylosuccinate synthetase, and that the resulting arabinofuranosyladenylosuccinate is cleaved to ara-AMP by adenylosuccinate lyase (1). The selective action of ara-A against HSV appears to be a consequence of the preferential inhibition of ara-ATP against HSV-1 and HSV-2 polymerases. Ara-ATP also inhibits normal cellular DNA polymerases, which may be the reason for its cellular toxicity. Also, it has been observed that ara-A is incorporated uniformly throughout the HSV-1 genome, which may result in defective viral DNA (50). 

The antiviral activity of (5)-DHPA in vivo was assessed in mice inoculated intranasaHy with vesicular stomatitis vims ( 5)-DHPA significantly increased survival from the infection. (5)-DHPA did not significantly reduce DNA, RNA, or protein synthesis and is not a substrate for adenosine deaminase of either bacterial or mammalian origin. However, (5)-DHPA strongly inhibits deamination of adenosine and ara-A by adenosine deaminase. Its mode of action may be inhibition of Vadenosyl-L-homocysteine hydrolase (61). Inhibition of SAH hydrolase results in the accumulation of SAH, which is a product inhibitor of Vadenosylmethionine-dependent methylation reactions. Such methylations are required for the maturation of vital mRNA, and hence inhibitors of SAH hydrolase may be expected to block vims repHcation by interference with viral mRNA methylation. 

The antiviral mechanism of action of acyclovir has been reviewed (72). Acyclovir is converted to the monophosphate in herpes vims-infected cells (but only to a limited extent in uninfected cells) by viral-induced thymidine kinase. It is then further phosphorylated by host cell guanosine monophosphate (GMP) kinase to acyclovir diphosphate [66341 -17-1], which in turn is phosphorylated to the triphosphate by unidentified cellular en2ymes. Acyclovir triphosphate [66341 -18-2] inhibits HSV-1 viral DNA polymerase but not cellular DNA polymerase. As a result, acyclovir is 300 to 3000 times more toxic to herpes vimses in an HSV-infected cell than to the cell itself. Studies have shown that a once-daily dose of acyclovir is effective in prevention of recurrent HSV-2 genital herpes (1). HCMV, on the other hand, is relatively uninhibited by acyclovir. 

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. 

Echinomycin (131) has been shown to be an antitumor agent and to have antiviral and antibacterial properties. Its structure elucidation represents a triumph for and mass spectral studies (75JA2497). It has been demonstrated that echinomycin functions by inhibiting RNA synthesis in organisms such as Staphylococcus aureus. Echinomycin, levomycin and actinoleutin are members of the quinoxaline-peptide antibiotic family and all contain one or more quinoxaline rings (67MI21402). 

Smith, T.J., et al. The site of attachment in human rhinovirus 14 for antiviral agents that inhibit uncoating. Science 233 1286-1293, 1986. 

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