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Document Page 477 fluenza, as it shows weak inhibition to bacterial, para influenza, and mammalian neuraminidases [91,93]. This is possibly due to the specific interactions of the 4-guanidino group within the subpocket of the active site of influenza neuraminidase that is not conserved in other neuraminidases. In bacterial neuraminidases [51] this pocket is much smaller, and would prevent the binding of the 4-guanidino group in this region of the active site. This is consistent with the proposition that the interactions of sialic acid with the active site of neuraminidases are function specific at the C4, C5, and C6 position of sialic acid and that modification at these positions confer specificity to the target enzyme [72]. Other approaches [94] to structure-based design of inhibitors have to date produced only millimolar inhibition of neuraminidase activity. V. Antiviral Activity In vitro inhibition of viral replication in tissue culture was demonstrated earlier [34] for the trifluro derivative of Neu5Ac2en, but its antiviral activity in vivo was not demonstrated [77]. As a consequence of this, efforts were directed towards hemagglutinin, which was then considered a better target for antiinfluenza drugs. The interest in neuraminidase inhibitors as anti-influenza drugs has only been revived with the success of 4-guanidino-Neu5Ac2en and its analogs in attenuating viral titer in mice when administered directly into the lungs [91,95]. A. Inhibition In Vitro Von Itzstein and co-workers [91] have shown that the 4-amino-and 4-guanidino-Neu5Ac2en inhibit influenza strains A/Singapore/1/57 and B/Victoria/102/95 in MDCK cells with IC 50 values (the concentration required to inhibit plaque formation in MDCK cells by 50%) of 1.5 mM and 0.065 mM (4amino) and 0.014 mM and 0.005 mM (4-guanidino) respectively. These IC 50 values, in particular for the 4-guanidino compound, are well below those found for amantadine, ribovarin, and Neu5Ac2en. Furthermore in comparison to Neu5Ac2en, the 4-guanidino-Neu5Ac2en inhibitor was 100-fold less active against human lysosomal sialidase and over 1000-fold more active against a wide range of clinical isolates of influenza A and B, including amantidine and rimantadine resistant variants [93]. The inhibition of virus replication in MDCK cells has been confirmed [96] and this knowledge prompted the extension of the inhibition studies to human respiratory epithelium cells in vitro [97], which indicated high antiviral activity for strains of A(HINI) and A(N3N2) isolates. They also found that delayed administration of the drug—after viral replication was well estab- http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_477.html [4/9/2004 12:26:55 AM]
Document Page 478 lished—was associated with inhibition of virus replication. However viral titer was higher (1.3 log 10 compared to 4.0 log 10 at 10 mg/mL concentration of the drug) for the delayed administration compared with viral titer when the drug was present throughout the period of viral exposure. The clinical significance of this in the treatment of established infections has yet to be explored in detail, although preliminary clinical trails [98] have indicated some positive results. B. Administration and Inhibition In Vivo The earlier work of Palase and Schulman [77] indicated that the failure in inhibiting viral replication in mice after intranasal and subcutaneous treatment with Neu5aC2en would also occur for Neu5Ac2en analogs. This failure of Neu5Ac2en as an antiviral treatment in animal models can now be ascribed to the rapid excretion of the compound [99] thereby not delivering sufficient concentration of the inhibitor to the infected tissue. It had been shown [91] that the antiviral activity in mice is considerably more, when the 4-guanidino compound is administered intranasally than when the drug is injected intraperitoneally. This can be attributed to the localization of sufficiently high concentration of inhibitor in the lining of the nasal and respiratory epithelia where influenza virus replication is believed to occur. Animal trials with ferrets challenged with influenza virus have shown the 4-guanidino Neu5Ac2en compound is effective in studies [91] involving prophylactic administration of the drug. When the drug is administrated intranasally, 50 μg/kg, twice daily, one day before infection with the virus and the succeeding six days, it substantially reduces virus titer in nasal washing and abolishes fever that usually appears 3 days after infection. The drug is currently undergoing clinical trials, and the initial results from a double blind, randomized, placebo-controlled trial using this compound have been positive both for early treatment and prophylaxis of experimental inoculation of human volunteers [98] with influenza A/Texas/91. C. Drug Resistance Although the active site of influenza virus has been conserved in all known field strains of the virus, the possibility of drug resistance needs to be addressed. Experience with influenza and other viruses, in particular HIV, have shown [100] that drug-resistant mutants arise very rapidly, resulting in the effectiveness of antiviral drugs being short lived. One attempted solution to the problem is the use of several drugs during therapy [101], making it more difficult for the virus the develop resistance. In the case of influenza virus, there have to date been no reports of drug resistance from field strains. However it has recently been reported [102,103] http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_478.html [4/9/2004 12:27:14 AM]
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Document Kininogen, 119 high molecu
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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