Inhibition of Influenza Virus

Influenza virus A is the primary causative agent responsible for serious cases of human influenza. The influenza infection is initiated by attachment of the virus to the mammalian cell membrane through a process known as hemagglutination. The hemagglutination process is a multivalent interaction between trimers of hemagglutinin (a carbohydrate binding protein present on the viral surface) with multiple sialic acid groups present on the surface of the mammalian epithelial cell. These sialic acid residues are parts of 

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Amino- and hydrazino-quinazolines exhibited antibacterial ac-tivity and a patent claim on the in vitro action of 2,4-diamino-quinazolines was rnade. The preparation of thiopegan derivatives as potential antimalarials and antibacterials deserves mention. Complete inhibition of influenza virus in vitro but not in vivo was shown by. 6,8-dichloro-2,4-dihydroxyquinazoline and other cyclic ureas. Activity against trachoma virus was also displayed by several 2-trichloromethylquinazolines. ... 

An overview of the role of the virus-associated glycoprotein sialidase (neuraminidase) and some of the most recent developments towards the discovery of anti-influenza drugs based on the inhibition of influenza virus sialidase is provided in this chapter. 

Compound 34 (BCZ-1812, RWJ-270201, peramivir) showed selective inhibition of influenza virus sialidases over bacterial and mammalian sialidases (Babu et al. 2000 Bantia et al. 2001 Sidwell and Smee 2002). Successful inhibition of influenza virus infectivity in vitro (Smee et al. 2001) and upon oral administration in vivo [mice (Bantia et al. 2001) and ferrets, reviewed in Sidwell and Smee 2002] led to human clinical trials of orally administered peramivir (Barroso et al. 2005). While orally administrated peramivir successfully completed animal studies and Phase I and Phase II clinical trials, in which the compound was showing neither major side effects nor toxicity (Sidwell and Smee 2002), preliminary results of the Phase III trials (June 2002) demonstrated no statistically significant difference in the primary efficacy endpoint, possibly due to low bioavailability (Barroso et al. 2005). 

Ryan DM, Ticehurst J, Dempsey M, Penn CR (1994) Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-iV-acetylneuraminic add) is consistent with extracellular actiivity of viral neuraminidase (sialidase), Antimicrob Agents Chemother 10 2270-2275... 

Pharmacology The proposed mechanism of action of zanamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. 

Palase P, Compans RW. Inhibition of influenza virus replication in tissue culture 2-deoxy-2,3-dehydro-N-trifluroacetylneuraminic acid (FANA) mechanism of action. J Gen Virol 1976 33 159-163. 

In many cases nucleic acid polymerases are zinc-dependent enzymes. Hutchinson et al.45 have drawn upon the use of phosphonoacetic acid and phosphonoformic acid and introduced mono- and bis-thiopyrophosphate. They propose that the inhibition of influenza virus occurs by inhibition of RNA transcriptase45. By using 31P-NMR they... 

Fig. 19. Inhibition of influenza virus A and B sialidases by cyclohexene-based amides 158 and 159. Numbers given in parentheses are IC50 values for NA(A) and NA(B), respectively. The IC50 values obtained for 1 under the same conditions were 0.005 pM for NA(A) and 0.004 pM for NA(B).

The potent and selective inhibition of influenza virus sialidase by 4-amino-... 

Bianco, A, Brufani, M, Manna, F, Melchioni, C, S3mthesis of a carbocychc siahc acid analogue for the inhibition of influenza virus neuraminidase, Carbohydr. Res., 332, 23-31, 2001. 

Inhibition of influenza virus attachment. Competition for cell receptor using a hexapeptide fusion sequence at the N-terminusof the haemagglutinin antireceptor ... 

Ge Q, Filip L, Bai A, Nguyen T, Eisen HN, Chen J (2004) Inhibition of influenza virus production in virus-infected mice by RNA interference. Proc Natl Acad Sci U S A 101 8676-8681... 

The first substrate-based influenza virus sialidase inhibitor described was Neu5Ac2en (6) [71, 72], It is proposed that the olefin in (6) mimics, to a certain extent, the conformation of the proposed sialosyl cation transition-state intermediate (4) [62,68,69], Neu5Ac2en shows reasonably potent inhibition of influenza virus sialidase (with a A j in the range of 10 5 to 10 6 M) in vitro... 

In a chicken embryo hemagglutination valence-reduction test, Yan et al. (2002) investigated the inhibition of influenza virus A3 by the Lamiaceae Mosla chinensis EO. The authors assessed the activity of the EO for treatment against pneumonia in experiments with mice and found that the cytopathic effect (CPE) caused by influenza virus A3 was reduced in Vero cells by this EO. The hemagglutination valence was reduced from 1 1280 to 1 20 and 1 160 at concentrations of 500, 250, and 50 mg/mL in 9-day-old chicken, respectively. At a dosage of 100 (ig/g/d, the therapeutic treatment of mice against pneumonia was successful. 

Nagai T, Miyaichi Y, Tomimori T et al (1990) Inhibition of influenza virus sialidase and anti-influenza virus activity by plant flavonoids. Chem Pharm Bull 38 1329-1332... 

In an in vitro fluorometric enzyme assay, 4-amino-4-deoxy-Neu5Ac2en 16 (A] 0.04 pM) [98,110] produced competitive inhibition of influenza virus sialidase... 

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