Mechanisms of action of antiviral drugs

Definition

Antiviral drugs are used to prevent the replication of viruses in the cells of the human body. Viruses, the smallest agents of infection, consist of either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and typically are enclosed within a protein coat (capsid). Viruses lack their own metabolism, so to replicate, they must infect a living organism (host) and use that host’s cellular machinery.

The viral life cycle is similar for most viruses. Attachment to the host cell is achieved through interaction between viral and host surface proteins. The virus crosses the host cell membrane (entry), the capsid proteins protecting the viral genome are shed (uncoating), and the genome is transcribed into mRNAs (messenger RNA), which are translated. After uncoating, retroviruses (which have the ability to replicate themselves in a host cell) require additional steps: converting the RNA genome to DNA (reverse transcription) and integration into the host genome (strand transfer). After genome replication, the virus self-assembles and is released from the cell by lysis or budding.

Therapies Against Viral Infection

Therapies for viral infections can be classified into agents (antivirals) that inhibit viral replication within the cell, agents (antibodies, virucides) that block viral infection of the host cell, and agents (immunomodulators) that modulate the host response to the viral infection. To selectively inhibit viral replication, drugs exploit the differences between viral and human proteins. Most antiviral drugs target viral nucleic acid synthesis.

Inhibition of Attachment, Entry, and Uncoating

The human immunodeficiency virus (HIV) drugs enfuvirtide and maraviroc are small molecules that inhibit the entry of a virus to its target cell by interacting with viral surface glycoproteins. Enfuvirtide is a peptide that is similar to the HIV glycoprotein gp41; it appears to block the conformational change in gp41 required for fusion and entry. Maraviroc binds to the HIV protein gp120, which prevents its interaction with the host chemokine receptor CCR5. The drug n-docosanol is a 22-carbon saturated fatty acid that appears to block entry of lipid-enveloped viruses into target cells.

Amantadine and rimantadine target the viral uncoating step by blocking matrix protein, which forms a transmembrane proton channel in the influenza A lipid envelope. After fusion with the host cell endosome, the passage of hydrogen ions through the proton channel into the virion acidifies the interior, which alters interactions among nucleocapsid proteins and initiates viral uncoating. Pleconaril is another drug that blocks viral uncoating; its high-affinity binding to a hydrophobic pocket of the main capsid protein increases capsid stability and inhibits release of the viral genome.

Inhibition of Genome Replication and Expression

Viral replication is most often targeted by drugs that inhibit the viral polymerase. Nucleoside and nucleotide analog drugs are used as substrates by the viral polymerase, the enzyme that links nucleotide monomers covalently into DNA or RNA. Nucleotides contain one or more phosphate groups, whereas nucleosides require intracellular phosphorylation before they can be incorporated into nucleic acid strand.

For example, acyclovir, an analog of the nucleoside guanosine, inhibits replication of herpes simplex virus (HSV) types 1 and 2 and varicella zoster virus (VZV). It lacks the 3 hydroxyl group needed to create a bond to the next nucleotide in the growing nucleic acid chain; therefore, it is a chain terminator of viral DNA elongation. Because it prevents binding of the normal substrate to the enzyme, it is a competitive inhibitor. Valacyclovir is a more bioavailable form of acyclovir; it is inactive until chemically converted within the cell (that is, as a prodrug of acyclovir). Other guanosine/guanine inhibitors include penciclovir (prodrug famciclovir); ganciclovir (prodrug valganciclovir), which is modified to increase activity against cytomegalovirus (CMV) infections; and ribavirin, which inhibits viral RNA polymerase activity and inhibits the 5 capping of viral mRNA. Ribavirin also appears to enhance the host T-cell-mediated immune response and to inhibit the host inosine monophosphate dehydrogenase, thereby decreasing the intracellular pool of guanosine triphosphate needed for viral replication and acting as a virus mutagen.

Penciclovir (prodrug famciclovir) is another guanine analog, but unlike acyclovir, it is sometimes incorporated into the DNA. It is active against VZV, HSV, and Epstein-Barr virus (EBV). Other nucleoside/nucleotide analogs include cidofovir, a cytosine analog that is active against HSV and poxviruses; vidarabine, an adenosine analog; and the thymidine analogs brivudine, idoxuridine, and trifluridine. Similarly, the reverse transcriptase of retroviruses can be inhibited by nucleotide/nucleoside inhibitors, including zidovudine (the first antiretroviral drug approved for HIV treatment), emtricitabine, abacavir, didanosine, and lamivudine. Retroviruses also require the enzyme integrase for stable integration of the viral DNA into the host genome. The drug raltegravir is the first integrase inhibitor approved for clinical use.

Viral replication can also be blocked by noncompetitive inhibition of the polymerase. Foscarnet is a pyrophosphate analog that binds the pyrophosphate-binding site of herpesvirus DNA polymerase and HIV reverse transcriptase. This binding blocks pyrophosphate cleavage from nucleotides, which prevents their incorporation into the DNA chain.

Fomivirsen is a 21-nucleotide antisense molecule complementary to the mRNA encoding intermediate-early region 2 of CMV, but it also appears to prevent attachment and viral DNA synthesis through unknown mechanisms. Antisense molecules bind to the target mRNA and block its translation. Fomivirsen is modified to block its degradation by nucleases. One of the oxygens in the phosphodiester backbone is replaced with a sulfur, making it a phosphorothioate.

Inhibition of Viral Maturation and Release

For many viruses, the maturation of viral proteins by a protease is essential before the virions are released. A number of drugs have been developed that inhibit the HIV protease by binding to its active site; they include tipranavir, indinavir, saquinavir, nelfinavir, and fosamprenavir.

Viral release is targeted by zanamivir and oseltamivir, which are sialic acid analogs that are competitive reversible inhibitors of neuraminidase, an enzyme expressed on the surface of influenza A and B viruses. Viral neuraminidases cleave sialic acid residues on host receptors recognized by viral hemagglutinin; this releases new viruses from the infected cell, allowing them to spread and infect other cells. Neuraminidase inhibitors, therefore, limit the spread of the virus.

Impact

Considerable progress has been made in the development of effective therapies for viral infections. Better understandings of the physiology of viral replication will reveal more drug targets and increase the therapeutic options for viral infections, especially for emerging viruses such as coronavirus and chronic viral diseases such as hepatitis B and C.

Following the COVID-19 pandemic that began in the early 2020s, a new series of antiviral drugs targeting the COVID-19 virus were developed and released. According to the Centers for Disease Control and Prevention (CDC) in 2024, three antiviral COVID-19 drugs were available. Paxlovid, also known as Nirmatrelvir with Ritonavir, and Lagevrio, also known as Molnupiravir, could be administered orally at home. Veklury, also known as Remdesivir, must be administered intravenously in a medical facility over a three-day period. Each COVID-19 antiviral worked to reduce the duration and severity of the illness.

Bibliography

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"If You Get Sick With COVID-19, Antiviral Treatments Can Protect You Against Severe Illness." Centers for Disease Control, 21 Dec. 2023, www.cdc.gov/ncird/whats-new/antiviral-treatments.html. Accessed 4 Feb. 2025.

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