Understanding the Three Major Modes of Action of Antiviral Drugs

Viral infections can be combated with antiviral drugs that target certain stages of the viral cycle. These drugs work by a variety of mechanisms to stop viral replication, make disease less painful and prevent infection. In this post, we discuss the 3 main mechanisms of action of antiviral agents, categorize antiviral drugs by mechanism and point to a few notable examples such as amantadine, interferon, ivermectin, molnupiravir, and zinc.

Antiviral Mechanism of Action

Antiviral therapies are carefully engineered to find holes in the viral lifecycle, the path a virus travels along to take host and replicate. But viruses are not bacteria and, rather than being obligate intracellular parasites, they rely almost entirely on the host's cells to multiply. That dependence renders antiviral drugs very difficult to construct, since they must distinguish between the virus and the host's normal cell life so as not to impair healthy cells. The most important mechanism of action for antiviral drugs:

Targeting Viral Proteins

Most antiviral drugs target viral proteins involved in replication. They are enzymes such as reverse transcriptase, protease and polymerase. Reverse transcriptase inhibitors (like zidovudine for HIV) impede retroviruses' translation of viral RNA into DNA. These protease inhibitors (such as ritonavir) block the cleavage of viral protein precursors so that functional viral particles are not formed. Polymerase inhibitors, like remdesivir for RNA viruses, stop the viral genome from copying. Such methods take advantage of the fact that the virus depends on these proteins to shut down its replication without very seriously compromising the host cell.

Modulating Host Immune Responses

Some antivirals act by activating the host's own natural immune system against viral infections. Interferons, for instance, are naturally occurring proteins that boost antiviral genes and send immune cells to infected sites. Medicines mimicking or exaggerating these reactions can make it even easier for the host to regulate and kill the virus.

Blocking Viral-Host Interactions

Entry inhibitors are a second important class of antivirals. These molecules stop the virus from attaching to or getting into the host cell. An HIV entry inhibitor called maraviroc, for example, interferes with the CCR5 receptor on host cells, which the virus prefers to attack. The same goes for drugs that disrupt the fusion machinery so that the virus cannot meld itself to the host cell membrane and infect itself.

These mechanisms are just a few examples of how the powerful tactics that antiviral agents use to disrupt the viral lifecycle without damaging host cells help to make the treatment efficacious and safe.

Classification of Antiviral Drugs According to Mechanism of Action

Antiviral drugs are classified primarily based on the specific stage of the viral lifecycle they target. This categorization helps researchers and clinicians understand their function and develop targeted therapies for specific viruses. The three major categories are:

Inhibition of Viral Entry or Fusion

Drugs in this category prevent viruses from gaining entry into host cells, an essential first step in infection. They work by targeting viral proteins or host cell receptors required for attachment and fusion. For example, enfuvirtide, an HIV entry inhibitor, blocks the virus's ability to fuse with the host cell membrane. Similarly, monoclonal antibodies against viral surface proteins can neutralize the virus before it infects the cell.

Inhibition of Viral Replication or Transcription

These agents disrupt the processes by which viruses replicate their genetic material or produce RNA. Examples include nucleoside analogs like acyclovir, which inhibits DNA replication in herpesviruses, and RNA polymerase inhibitors like remdesivir, which target RNA viruses such as SARS-CoV. By halting genome synthesis, these drugs suppress viral propagation within the host.

Inhibition of Viral Assembly or Release

This category includes drugs that prevent the formation of new viral particles or their release from infected cells. Protease inhibitors, such as those used for HIV and hepatitis C, interfere with the cleavage of viral polyproteins, essential for creating infectious virions. Neuraminidase inhibitors like oseltamivir block influenza viruses from exiting host cells, curbing the infection's spread.

Table.1 SARS-CoV related products at BOC Sciences.

Amantadine Antiviral Mechanism of Action

Amantadine is one of the earliest antiviral drugs developed, primarily used to treat influenza A. Its mechanism of action involves blocking the M2 proton channel of the influenza virus. This channel is essential for uncoating the viral RNA within host cells, a critical step in the viral lifecycle. By inhibiting this process, amantadine prevents the release of viral genetic material, halting replication. However, widespread resistance has limited its use in recent years, underscoring the need for new strategies to overcome antiviral resistance.

Interferon Antiviral Mechanism

Interferons (IFNs) are naturally occurring proteins produced by host cells in response to viral infections. These proteins have a broad-spectrum antiviral mechanism of action, making them effective against multiple viruses. Interferons work by:

• Enhancing the expression of antiviral genes that inhibit viral replication.
• Modulating immune responses to recruit immune cells to the site of infection.
• Inducing apoptosis in infected cells to limit viral spread.

Interferons have been used in the treatment of hepatitis B and hepatitis C, certain cancers, and as experimental therapies for emerging viral infections.

Ivermectin Antiviral Mechanism

Originally an antiparasitic drug, ivermectin has shown potential antiviral properties against several viruses, including SARS-CoV-2. Its antiviral mechanism is believed to involve inhibition of the importin (IMP) α/β1 nuclear transport proteins. These proteins are used by viruses to transport their viral proteins into the host cell nucleus, where they suppress host antiviral responses. By blocking this pathway, ivermectin disrupts viral replication and enhances host immunity.

Molnupiravir Antiviral Mechanism

Molnupiravir is a novel antiviral drug developed to combat RNA viruses, including SARS-CoV-2. Its mechanism of action involves introducing errors into the viral RNA during replication, a process known as lethal mutagenesis. Molnupiravir is converted into its active form, which resembles natural RNA nucleosides. When incorporated into viral RNA, it causes extensive mutations, rendering the virus non-infectious. This innovative approach has proven effective in reducing viral loads and disease severity in clinical studies.

Zinc Antiviral Mechanism

Zinc, an essential trace element, exhibits broad-spectrum antiviral activity. Its mechanism of action involves disrupting viral proteases and polymerases, enzymes critical for viral replication. Zinc also enhances the host immune response by stabilizing cell membranes, reducing inflammation, and modulating cytokine production. In combination with zinc ionophores, such as hydroxychloroquine, zinc's intracellular concentration increases, further amplifying its antiviral effects. This dual role as both a direct antiviral agent and an immune modulator makes zinc a valuable component in combating viral infections.

Summary

Understanding the mechanisms of action of antiviral drugs provides valuable insights into their design, application, and limitations. From disrupting viral entry to inducing lethal mutagenesis, these drugs play a pivotal role in controlling viral diseases. With ongoing research and innovation, the future of antiviral therapy holds promise for addressing both existing and emerging viral threats.

Reference

• Kausar, Shamaila, et al., A review: Mechanism of action of antiviral drugs. International journal of immunopathology and pharmacology 35 (2021): 20587384211002621.

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