Chemotherapy of Viral Infections

Viruses essentially consist of genetic material (nucleic acids) and a capsular envelope made up of proteins, often with a coat of a phospholipid (PL) bilayer with embedded proteins. They lack a metabolic system and depend on the infected cell for their growth and replication. Targeted therapeutic suppression of viral replication requires selective inhibition of those metabolic processes that specifically serve viral replication in infected cells.

Viral replication as exemplified by herpes simplex viruses (A).

1.The viral particle attaches to the host cell membrane (adsorption) via envelope glycoproteins that make contact with specific structures of the cell membrane.

2.The viral coat fuses with the plasmalemma of host cells and the nucleocapsid (nucleic acid plus capsule) enters the cell interior (penetration).

3.The capsule opens (“uncoating”) near the nuclear pores and viral DNA moves into the cell nucleus. The genetic material of the virus can now direct the cell’s metabolic system.

4a. Nucleic acid synthesis: The genetic material (DNA in this instance) is replicated and RNA is produced for the purpose of protein synthesis.

4b. The proteins are used as “viral enzymes” catalyzing viral multiplication (e.g., DNA polymerase and thymidine kinase), as capsomers, or as coat components, or are incorporated into the host cell membrane.

5.Individual components are assembled into new virus particles (maturation).

6.Release of daughter viruses results in spread of virus inside and outside the or-

ganism.

With herpesviruses, replication entails host cell destruction and development of disease symptoms.

Antiviral mechanisms (A). The organism can disrupt viral replication with the aid of cytotoxic T-lymphocytes that recognize and destroy virus-producing cells (presenting viral proteins on their surface, p.304) or by means of antibodies that bind to and inactivate extracellular virus particles. Vaccinations are designed to activate specific immune defenses.

Interferons (IFN) are glycoproteins that, among other products, are released from virus-infected cells. In neighboring cells, interferon stimulates the production of “antiviral proteins.” These inhibit the synthesis of viral proteins by (preferential) destruction of viral DNA or by suppressing its translation. Interferons are not directed against a specific virus, but have a broad spectrum of antiviral action that is, however, species-specific. Thus, interferon for use in humans must be obtained from cells of human origin, such as leukocytes (IFN-α), fibroblasts (IFN-β), or lymphocytes (IFN-γ). Interferons are used in the treatment of certain viral diseases, as well as malignant neoplasias and autoimmune diseases; e.g., IFN-α for the treatment of chronic hepatitis C and hairy cell leukemia; and IFN-β in severe herpes virus infections and multiple sclerosis.

Virustatic antimetabolites are “false” DNA building blocks (B) or nucleosides. A nucleoside (e.g., thymidine) consists of a nucleobase (e.g., thymine) and the sugar deoxyribose. In antimetabolites, one of the components is defective. In the body, the abnormal nucleosides undergo bioactivation by attachment of three phosphate residues (p.289).

Idoxuridine and congeners are incorporated into DNA with deleterious results. This also applies to the synthesis of human DNA. Therefore, idoxuridine and analogues are suitable only for topical use (e.g., in herpes simplex keratitis).

Among virustatic antimetabolites, aciclovir (A) has both specificity of the highest degree and optimal tolerability because it undergoes bioactivation only in infected cells, where it preferentially inhibits viral DNA synthesis. (1) A virally coded thymidine kinase (specific to herpes simplex and varicel- la-zoster viruses) performs the initial phosphorylation step; the remaining two phosphate residues are attached by cellular kinases. (2) The polar phosphate residues render aciclovir triphosphate membraneimpermeable and cause it to accumulate in infected cells. (3) Aciclovir triphosphate is a preferred substrate of viral DNA polymerase; it inhibits enzyme activity and, following its incorporation into viral DNA, induces strand breakage because it lacks the 3′-OH group of deoxyribose that is required for the attachment of additional nucleotides. The high therapeutic value of aciclovir is evident in severe infections with herpes simplex viruses (e.g., encephalitis, generalized infection) and varicella-zoster viruses (e.g., severe herpes zoster). In these cases, it can be given by i.v. infusion. Aciclovir may also be given orally despite its incomplete (15–30%) enteral absorption. In addition, it has topical uses. Because host DNA synthesis remains unaffected, adverse effects do not include bone marrow depression.

In valaciclovir, the hydroxyl group is esterified with the amino acid L-valine (p.287B). This allows utilization of an enteral dipeptide transporter, leading to an enteral absorption rate almost double that of aciclovir. Subsequent cleavage of the valine residue yields aciclovir.

Famciclovir is an antiherpetic prodrug (active species penciclovir) with good oral bioavailability.

Ganciclovir (structure on p.287B) is used in the treatment of severe infections with cytomegaly viruses (also belonging to the herpes group); these do not form thymidine kinase, phosphorylation being initiated by a different viral enzyme. Ganciclovir is less well tolerated and, not infrequently, produ-

ces leukopenia and thrombopenia. It is infused or administered orally as a valine ester (valganciclovir).

Foscarnet represents a diphosphate analogue. Incorporation of nucleotide into a DNA strand entails cleavage of a diphosphate residue. Foscarnet inhibits DNA polymerase by interacting with its binding site for the diphosphate group. Indications: systemic therapy in severe cytomegaly infections in AIDS patients; local therapy of herpes simplex infections.

Drugs against influenza viruses (C). Amantadine specifically affects the replication of influenza A (RNA) viruses, the causative agents of true influenza. These viruses are endocytosed into the cell. Release of viral RNA requires protons from the acidic content of endosomes to penetrate into the virus. Amantadine blocks a channel protein in the viral coat that permits influx of protons. Thus, “uncoating” is prevented. The drug is used for prophylaxis and, hence, must be taken before the outbreak of symptoms. It is also an antiparkinsonian drug (p.188).

Neuraminidase inhibitors prevent the release of influenza A and B viruses. Normally, the viral neuraminidase splits off N-acetyl- neuraminic (sialic) acid residues on the cellular surface coat, thereby enabling newly formed viral particles to be detached from the host cell. Zanamivir is given by inhalation; oseltamivir is suitable for oral administration because it is an ester prodrug. Possible uses include treatment and prophylaxis of influenza virus infections.