Chapter 12 : Antiherpesvirus, Anti-Hepatitis Virus, and Anti-Respiratory Virus Agents

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This chapter reviews agents which have been, or are being, developed to treat herpesvirus, hepatitis virus, and respiratory virus infections. Detailed information is provided for approved agents and those in more advanced stages of clinical development. Agents in phase I human studies or promising approaches which are still in preclinical development are described briefly. The anti-herpes simplex virus (HSV) activity of acyclovir demonstrated that analogs of guanosine were active and that acyclic side chains could substitute for the ribose moiety, conferring specificity by the selective uptake and activation of acyclovir in HSV-infected cells. Thymidine kinase-deficient or -altered HSV or varicella-zoster virus (VZV) isolates resistant to acyclovir remain susceptible in vitro to foscarnet, cidofovir, and brivudine but are fully cross-resistant to ganciclovir and famciclovir. The more convenient dosing schedule of famciclovir and the potentially shorter duration of postherpetic neuralgia argue in favor of employing famciclovir or valacyclovir for herpes zoster, particularly in older individuals, in whom the complication of postherpetic neuralgia is more frequent. Cidofovir has been primarily developed as an anti-CMV agent but has broad antiherpesvirus activity. New antiherpesvirus drugs include inhibitors of immediate early gene expression, nonnucleoside DNA polymerase inhibitors, helicase-primase inhibitors, inhibitors of protein-protein interactions among DNA replication proteins, and inhibitors of assembly, encapsidation, and nuclear egress. The chapter describes agents that are primarily or exclusively directed at treatment of hepatitis virus infection. Antiviral activities of ribavirin are also described.

Citation: Yin M, Brust J, Tieu H, Hammer S. 2009. Antiherpesvirus, Anti-Hepatitis Virus, and Anti-Respiratory Virus Agents, p 217-264. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch12
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Image of FIGURE 1

Chemical structures of antiherpesvirus agents.

Citation: Yin M, Brust J, Tieu H, Hammer S. 2009. Antiherpesvirus, Anti-Hepatitis Virus, and Anti-Respiratory Virus Agents, p 217-264. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch12
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Image of FIGURE 2

Chemical structures of anti-HCV agents.

Citation: Yin M, Brust J, Tieu H, Hammer S. 2009. Antiherpesvirus, Anti-Hepatitis Virus, and Anti-Respiratory Virus Agents, p 217-264. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch12
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Image of FIGURE 3

Inhibition of HCV replication cycle by antiviral agents. After surface-bound HCV is internalized via receptor-mediated endocytosis, fusion of the viral envelope and cellular endosomal membrane occurs and the HCV RNA is passaged to the endoplasmic reticulum (ER). The internal ribosome entry site (IRES) directs the binding of the viral RNA to cytoplasmic ribosomal subunits and initiates translation. The large polyprotein precursor is processed by cellular and viral proteases into structural and nonstructural proteins. The viral NS3/NS4A protease is the target of HCV protease inhibitors. The viral NS5B enzyme, RNA polymerase, is responsible for the initial synthesis of a complementary negative-strand RNA template and the subsequent synthesis of positive-strand RNA [(+)RNA] and is the target of the HCV polymerase inhibitors. The final step of HCV replication consists of viral assembly and release. α-Glucosidase I is a host enzyme that is essential for the proper glycosylation of viral envelope proteins, and is the target of α-glucosidase inhibitors. MW, membranous web. (Adapted from reference with permission [http://clinicaloptions.com/hiventry].)

Citation: Yin M, Brust J, Tieu H, Hammer S. 2009. Antiherpesvirus, Anti-Hepatitis Virus, and Anti-Respiratory Virus Agents, p 217-264. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch12
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Image of FIGURE 4

Chemical structures of anti-HBV agents.

Citation: Yin M, Brust J, Tieu H, Hammer S. 2009. Antiherpesvirus, Anti-Hepatitis Virus, and Anti-Respiratory Virus Agents, p 217-264. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch12
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Image of FIGURE 5

Chemical structures of amantadine (left) and rimantadine (right).

Citation: Yin M, Brust J, Tieu H, Hammer S. 2009. Antiherpesvirus, Anti-Hepatitis Virus, and Anti-Respiratory Virus Agents, p 217-264. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch12
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Image of FIGURE 6

Chemical structures of anti-influenza virus agents.

Citation: Yin M, Brust J, Tieu H, Hammer S. 2009. Antiherpesvirus, Anti-Hepatitis Virus, and Anti-Respiratory Virus Agents, p 217-264. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch12
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