Inhibition of Viral Nucleic Acid Synthesis

Many antiviral compounds are nucleoside or nucleotide analogues whose mechanism of action is inhibition of viral nucleic acid synthesis. Nucleoside analogues such as acyclovir and penciclovir require phosphorylation to the monophosphate, which requires a thymidine kinase coded by herpes simplex virus and not present in uninfected cells.¹ Cellular kinases phosphorylate acyclovir to the triphosphate moiety, which inhibits the viral DNA polymerase and is incorporated into viral DNA as a chain terminator, thus inhibiting viral DNA synthesis. The requirement for a virus-encoded enzyme provides a virus-specific mechanism of action. Herpes simplex viruses that lack a thymidine kinase are resistant to acyclovir and penciclovir.²

Cidofovir is a monophosphorylated nucleotide analogue that does not require a virus-coded thymidine kinase for its activity. It utilizes cellular kinases to convert it to a diphosphate moiety that inhibits viral DNA polymerase and also causes premature chain termination. It is active against viruses that lack thymidine kinase and are therefore resistant to acyclovir and penciclovir.³

Foscarnet is not a nucleoside or nucleotide analogue but rather a pyrophosphate that blocks the pyrophosphate-binding site on the viral DNA polymerase. Thus, it does not require intracellular metabolism for its anti-herpesvirus activity.⁴

A novel mechanism of action, inhibition of the helicase-primase complex is manifested by amenamevir⁵ and pritelivir,⁶ which are active against herpes simplex viruses types 1 and 2. The helicase-primase complex is a heterotrimer consisting of helicase, primase, and cofactor subunits that are essential for DNA replication. Amenamevir and pritelivir are not nucleoside analogues, do not require phosphorylation by thymidine kinase, and are therefore active against viruses that are resistant to acyclovir and penciclovir because of thymidine kinase deficiencies. Amenamevir and pritelivir are undergoing clinical studies in suppression and treatment of genital herpes (see Chapter 45).

Letermovir is an antiviral agent with activity against cytomegalovirus through inhibition of the viral terminase enzyme complex, which results in interference with processing and blockage of viral DNA.⁷ It does not inhibit the viral DNA polymerase and is therefore active against cytomegalovirus strains resistant to ganciclovir, cidofovir, and foscarnet.

In HIV infection, nucleoside and nucleotide analogues inhibit viral complementary DNA synthesis through inhibition of reverse transcriptase. These drugs must be phosphorylated to the triphosphate moieties for anti-HIV activity. They include zidovudine, tenofovir, emtricitabine, and abacavir. Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) also bind to reverse transcriptase but do so in a pocket far from the active site, in contrast to the nucleoside and nucleotide analogues. NNRTIs include nevirapine and efavirenz.

RNA Antisense Nucleotides

Antisense nucleotides inhibit transcription of messenger (m)RNA and can be utilized to inhibit replication of viruses. Fomivirsen is an antisense oligonucleotide that is complementary to a sequence in mRNA transcripts of the major immediate-early region 2 of cytomegalovirus.⁸ It is administered intravitreally to treat cytomegaloviral retinitis in HIV-infected patients who have failed or are intolerant to other treatments. Because of its unique antiviral mechanism of action, fomivirsen is active against cytomegaloviral strains that are resistant to ganciclovir, foscarnet, or cidofovir.

Viral Entry Inhibition

Inhibition of attachment of virus to its cellular reception or viral entry is an important mechanism for antiviral activity. Maraviroc is an allosteric inhibitor that interferes with attachment of HIV type 1 (HIV-1) to the CCR5 cellular chemokine receptor. Enfuvirtide is a synthetic peptide that inhibits gp41-mediated fusion of HIV-1 with the cell membrane and thus blocks virus entry (see Chapter 130).

Protease Inhibition

Many viruses require proteolytic cleavage of polypeptide precursors to activate essential viral proteins. For HIV-1, there are 10 clinically utilized inhibitors of such protease activity, which are important components of combination antiretroviral regimens. These protease inhibitors include ritonavir, nelfinavir, and atazanavir.

Boceprevir⁹ and telaprevir¹⁰ are peptidomimetics that inhibit the NS3/4A protease of hepatitis C virus by forming reversible covalent bonds with the NS3 active site. Multiple additional protease inhibitors against hepatitis C virus are under clinical development.

Integrase Inhibition

Integrase is an enzymatic activity required for integration of the HIV-1 genome into the genome of host cells, thus maintaining stability of the viral genome in the host. This function is inhibited by raltegravir and represents a relatively new category of antiviral activity (see Chapter 130).

Inhibition of Uncoating of Virus

The adamantane compounds amantadine¹¹ and rimantadine¹² interfere with the function of the M2 protein of influenza A virus and inhibit uncoating of influenza virus shortly after entry of virus into cells.^11,12 Single amino acid changes can render viruses resistant to the adamantanes, as is the case with currently circulating (2013-2014) influenza A viruses.¹³

Inhibition of Virus Release

The neuraminidase inhibitors oseltamivir and zanamivir interfere with release of influenza A and B from infected cells.^14,15 Neuraminidase prevents the clumping of released virus, and thus inhibition of this enzyme retards the cell-to-cell movement of virus.