Antiviral agents protease inhibitors

Patick AK, Potts KE (1998) Protease inhibitors as antiviral agents. Clin Microbiol Rev 4 614—627... 

Hurwitz SJ, Schinazi RF (2002) Development of a pharmacodynamic model for HIV treatment with nucleoside reverse transcriptase and protease inhibitors. Antiviral Res 56 115-127 Hurwitz SJ, Tennant BC, Korba BE, Gerin JL, Schinazi RF (1998) Pharmacodynamics of (—)-beta-2, 3 -dideoxy-3 -thiacytidine in chronically virus-infected woodchucks compared to its pharmacodynamics in humans, Antimicrob Agents Chemother 42 2804-2809 Hurwitz SJ, Otto MJ, Schinazi RF (2005) Comparative pharmacokinetics of Racivir, (+/-)-beta-2, 3 -dideoxy-5-fluoro-3 -thiacytidine in rats, rabbits, dogs, monkeys and HIV-infected humans, Antivir Chem Chemother 16 117-127... 

Lin K, Pemi RB, Kwong AD, Lin C (2006) VX-950, a novel hepatitis C vims (HCV) NS3 A protease inhibitor, exhibits potent antiviral activities in HCV repUcon cells. Antimicrob Agents Chemother 50 1813-1822... 

In this chapter, we have described the spectrum of antiviral activities that have been discovered beyond the world of nucleoside analogues, protease and fusion inhibitors. The compounds and mechanisms described here may one day add significantly to the armamentarium of antiviral agents, not only against Herpes Simplex, Hepatitis B and Human Immunodeficiency Virus, but also against Hepatitis C and Human Cytomegalovirus. 

Supuran CT, Casini A, Scozzafava A. Protease inhibitors of the sulfonamide type anticancer, anti-inflammatory, and antiviral agents. Med Res Rev 2003 23 535-58. 

The replicative cycle of HIV presents many opportunities for the targeting of antiviral agents. The drugs in clinical use are classified as nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NTRTIs), and protease inhibitors (PI). 

Although any of these seven steps could be a druggable target, most of the antiviral agents clinically employed for non-AIDS infections act on the synthesis or assembly of either purines or pyrimidines (steps 3 and 4). For AIDS, reverse transcriptase inhibitors block transcription of the HIV RNA genome into DNA, thereby preventing synthesis of viral mRNA and protein protease inhibitors act on the synthesis of late proteins (steps 5 and 6). 

Proteases also are involved in viral maturation. For example, in picomavirus replication the virus RNA is translated into large virus precursor polypeptides. These then are cleaved by a viral protease(s) into the viral proteins (26,27). This opens the possibility that specific inhibitors for the viral processing protease could be used as antiviral agents. 

The preceding three antiviral agents tend to differ form each other by only relatively small structural details. The next protease inhibitor includes some significant structural differences though it shares a similar central aminoalcohol sequence that is presumably responsible for its activity. Construction of one end of the molecule begins with protection of the carbonyl function in p-bromobenzaldehyde (27) as its methyl acetal (28) by treatment with methanol in the presence of acid. Reaction of that intermediate with the Grignard reagent from 4-bromopyridine leads to unusual... 

The design of the peptidomimetic antiviral agent (Chapter 1) ultimately traces back to the fact that structures of these protease inhibitors in some way act as surrogates for the natural substrate enzyme. The recent protease... 

As lymphocytes, monocytes, and macrophages are the primary targets for viral infection, the penetration of antiviral agents is important. Lymphocytes and monocytes are indicated as peripheral blood mononuclear cells (PBMC). The preparation of control PBMC from blood was reported in considerable detail by Jemal et al. [38], In addition, a validated assay for the determination of ATA in PBMC was developed. The determination of protease inhibitors in hmnan PBMC was reported by several groups [39-40]. After LLE, the analytes were analysed by LC-MS. Both methods enable the intra-cellular determination of the analytes and can be applied for TDM and pharmacokinetic studies. 

New antiviral agents have been based on virus-specific targets, especially the viral enzymes that are involved in the viral life cycle, i.e. responsible for the production of infectious viral particles. Research has focused on virus-encoded proteases that fulfil this role. Thus, specific inhibitors of HIV, herpesvirus and hepatitis C virus proteases are now known. Examples of clinically approved HIV pro-... 

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