Viral replication inhibition

The nonnucleoside reverse transcriptase inhibitors (NNRTIs), used in the treatment of AIDS, provide interesting examples of clinically relevant noncompetitive inhibitors. The causative agent of AIDS, HIV, belongs to a virus family that relies on an RNA-based genetic system. Replication of the vims requires reverse transcription of the viral genomic RNA into DNA, which is then incorporated into the genome of the infected host cell. Reverse transcription is catalyzed by a virally encoded nucleic acid polymerase, known as reverse transcriptase (RT). This enzyme is critical for viral replication inhibition of HIV RT is therefore an effective mechanism for abrogating infection in patients. 

The principal biological actions of type I IFNs include inhibition of viral replication, inhibition of cell proliferation, increase in the lytic potential of NK cells and the modulation of MHC molecule expression. They increase the expression of MHC class I molecules and decrease the expression of MHC class II molecules. 

Other components of the innate response include natural killer (NK) cells and a number of cytokines. NK cells lyse certain types of tumor cells and virally infected cells and are a rich source of immune interferon (interferon-y), which stimulates macrophages and T cells hence they are thought to play an important role in host resistance to both neoplastic and viral disease. Type I interferons (interferon a and interferon P) are produced by a number of different cell types and appear very rapidly after viral infection. Type I interferons inhibit viral replication, inhibit cell proliferation, and increase the lytic potential of NK cells and therefore play a role in controlling viral and neoplastic disease. Several cytokines are important in the initiation of inflammatory responses. Those that have received the most attention include tumor necrosis factor alpha (TNFa), interleukin (IL)-1, and IL-6. There are also a number of chemotactic cytokines (including IL-8), called chemokines, which help to mobilize immune cells to the site of injury. 

Viruses are small infectious agents composed of a nucleic acid genome (DNA or RNA) encased by structural proteins and in some cases a lipid envelope. They are the causative agents of a number of human infectious diseases, the most important for public health today being acquired immunodeficiency syndrome (AIDS), hepatitis, influenza, measles, and vituses causing diarrhoea (e.g., rotavirus). In addition, certain viruses contribute to the development of cancer. Antiviral drugs inhibit viral replication by specifically targeting viral enzymes or functions and are used to treat specific virus-associated diseases. 

Acyclovir (Zovirax) and penciclovir (Denavir) are the only topical antiviral dragp currently available These dragp inhibit viral replication. Acyclovir is used in the treatment of initial episodes of genital herpes, as well as heqies simplex virus infections in immunocompromised patients (patients with an immune system incapable of fighting infection). Penciclovir is used for the treatment of recurrent herpes labialis (cold sores) in adults. 

Viral replication, packaging and release. Drug Disc Today 1 388-397 Meindl P, Tuppy H (1969) 2-Deoxy-2,3-dehydrosialic acids. II. Competitive inhibition of Vibrio cholerae neuraminidase by 2-deoxy-2,3-dehydro-V-acyIneuraminic acids. Hoppe-Seyler s Z Physiol Chem 350 1088-1092... 

Env sequences both temporally and between patients. Two drugs that target HIV-1 entry, enfuvirtide and maraviroc, are now licensed for treatment of HIV-1 infection. The efficacy of these drugs validates entry as a point of intervention in viral hfe cycles and, in the context of HIV treatment, contributes to the growing armamentarium of antivirals which, in multidrug combinations, can effectively inhibit viral replication and prevent disease progression. 

In conclusion, IFNs have proven to be invaluable tools in the fight against chronic viral hepatitis. In these indications, their antiviral properties play a major role and it remains unclear whether their immunomodulatory properties are also important. Disappointing results obtained with purely immunomodulatory molecules, such as interleukins or Toll-like receptor agonists suggest that, if immunomodulation plays any role, potent inhibition of viral replication is also needed. The role of IFNs in the treatment of viral infections other than hepatitis B and C remains elusive. 

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Zhu Y, CuUen JM, Aldrich CE, SaputelU J, MiUer D, Seeger C, Mason WS, JUbert AR (2004) Adenovirus-based gene therapy during clevudine treatment of woodchucks chronically infected with woodchuck hepatitis virus. Virology 327 26 0 zu Putlitz J, Wieland S, Blum HE, Wands JR (1998) Antisense RNA complementary to hepatitis B virus specifically inhibits viral replication. Gastroenterology 115 702-713... 

M. G., Westbrook, L. S., Shannon, W. M., and Kende, M., Development of injectable, controlled-release poly(I.C) microcapsules for the inhibition of viral replication, Proc. Int. Symp. Control. Rel. Bioact. Mater.. 14. 275, 1987. 

HCV NS5B polymerase is an RNA-dependent RNA polymerase that is essential for viral replication. Thus, the inhibition of this enzyme offers a potential treatment for hepatitis C infection. Beaulieu et al. [51] report on the parallel optimization of enzyme inhibition potency and physical properties. In the first stage of hit characteri-... 

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