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Mechanism of Action of Antiviral Drugs

By
Sourav Bio

What are Antiviral Drugs?

Antiviral drugs represent a category of therapeutic agents specifically designed to counteract viral infections. Viruses, which are obligate intracellular parasites, are a predominant cause of morbidity and mortality in humans, animals, and plants. Their pathogenicity ranges from self-limiting conditions to severe, life-threatening diseases.

Unlike other microorganisms, viruses are devoid of the necessary enzymatic machinery for replication and the synthesis of their structural components. Instead, they exploit the cellular machinery of the host, effectively commandeering it for their own purposes. This ‘hijacking’ nature of viruses poses a significant challenge for drug development. The intricate relationship between the virus and its host cell means that any therapeutic agent targeting the virus has the potential to harm the host cell as well. Thus, the primary objective of antiviral drug development is to achieve selective toxicity, wherein the drug impedes viral functions without detrimentally affecting the host cell.

Recent advancements in molecular biology have provided profound insights into the replication cycles of viruses and the three-dimensional configurations of viral molecules. This knowledge has been instrumental in the design of specific and potent antiviral agents. The strategies employed in the development of antiviral drugs can be broadly categorized into two approaches: those that target the virus directly and those that target host cell factors.

Direct antiviral agents encompass a wide array of inhibitors, including:

  1. Virus attachment inhibitors
  2. Virus entry inhibitors
  3. Uncoating inhibitors
  4. Polymerase inhibitors
  5. Protease inhibitors
  6. Nucleoside and nucleotide reverse transcriptase inhibitors
  7. Integrase inhibitors

Notably, several of these inhibitors, such as protease inhibitors (e.g., ritonavir, atazanavir, and darunavir), viral DNA polymerase inhibitors (e.g., acyclovir, tenofovir, valganciclovir, and valacyclovir), and integrase inhibitors (e.g., raltegravir), have achieved significant commercial success, as evidenced by their inclusion in the list of top-selling drugs in the 2010s.

However, the antiviral drug landscape is not without its challenges. Despite the availability of drugs for conditions like herpesviruses, influenza, hepatitis C, and HIV, many viral infections still lack effective treatments. The mechanism of action for most antiviral drugs involves their conversion to triphosphate, subsequently inhibiting viral DNA synthesis.

In conclusion, antiviral drugs play a pivotal role in the medical arsenal against viral infections. Their development is a testament to the advancements in molecular biology and the relentless pursuit of science to combat these pathogenic entities.

Virus Structure and Replication

Viruses are intricate entities characterized by their unique structure and replication mechanisms. At the core of a virus lies its genome, which is composed of nucleic acid. This nucleic acid can be either DNA or RNA, but never both simultaneously. Encasing this genome is a proteinaceous structure known as the capsid. This protective shell ensures the stability and integrity of the viral genome. Furthermore, many animal viruses possess an additional lipid envelope, which is often studded with protein spikes. These protein spikes play a crucial role in facilitating the virus’s attachment to host cells.

The replication cycle of a virus, often referred to as its life cycle, is a multi-step process that ensures the propagation of the virus within the host. This cycle can be delineated into the following stages:

  1. Attachment: The initial phase involves the virus recognizing and binding to specific receptors on the surface of a susceptible host cell. This recognition is mediated by interactions between viral proteins and host cell receptors.
  2. Entry: Following attachment, the virus undergoes fusion with the host cell membrane, facilitating its entry into the cell.
  3. Uncoating: Once inside the host cell, the virus undergoes a process called uncoating. During this phase, the viral nucleic acid is released from its protective capsid, making it accessible for replication.
  4. Replication and Protein Synthesis: Utilizing the host cell’s machinery, the viral nucleic acid orchestrates the synthesis of viral RNA or DNA and proteins. This ensures the generation of components necessary for the assembly of new virions.
  5. Assembly: Newly synthesized viral components come together to form complete virion particles. This assembly process ensures that each virion is equipped with the necessary components to infect other cells.
  6. Release: The final stage of the viral life cycle involves the exit of newly formed virion particles from the host cell. This release can occur through various mechanisms, including cell lysis or budding.

In essence, the viral nucleic acid commandeers the host cell’s machinery to produce components essential for the formation of new, infectious virions. This intricate process underscores the remarkable adaptability and efficiency of viruses in ensuring their propagation within host organisms.

Steps of viral infections

Viral infections are intricate processes that involve a series of well-coordinated steps, allowing the virus to enter, replicate within, and eventually exit the host cell. The life cycle of a virus can be delineated into the following sequential stages:

  1. Viral Attachment:
    • This is the initial phase where the virus recognizes and binds to specific receptors on the surface of a susceptible host cell. This interaction facilitates the subsequent entry of the virus into the cell.
  2. Invasion (Penetration):
    • Following attachment, the virus introduces its genetic material into the host cell. This can occur through direct penetration of the host cell membrane or via endocytosis, where the host cell engulfs the virus in a vesicle.
  3. Uncoating:
    • Once inside the host cell, the virus undergoes a process called uncoating. During this phase, the viral nucleic acid (either DNA or RNA) is released from its protective protein coat, making it accessible for replication.
  4. Replication:
    • Utilizing the host cell’s machinery, the viral nucleic acid orchestrates the synthesis of viral RNA or DNA. This ensures the generation of components necessary for the assembly of new virions. During this stage, the viral genome is replicated, and viral proteins are synthesized.
  5. Assembly:
    • Newly synthesized viral components come together to form complete virion particles. This assembly process ensures that each virion is equipped with the necessary components to infect other cells.
  6. Release:
    • The final stage of the viral life cycle involves the exit of newly formed virion particles from the host cell. This release can occur through various mechanisms:
      • Lysis: The host cell breaks open, releasing the virions.
      • Apoptosis: The host cell undergoes programmed cell death, leading to the release of virions.
      • Budding: Virions exit the host cell by pushing out through the cell membrane, acquiring a lipid envelope in the process.

In essence, the viral life cycle is a meticulous process that ensures the propagation of the virus within the host organism. Each stage is crucial for the successful infection and spread of the virus to other cells, underscoring the importance of understanding these processes in the development of antiviral therapies.

Mechanisms of Action of Antiviral Drugs

Antiviral drugs are specialized therapeutic agents designed to inhibit viral replication. Rather than directly destroying or inactivating the virus, these drugs interfere with specific phases of the viral life cycle. The mechanisms of action of antiviral drugs can be broadly categorized based on their target: the virus itself or the host cell factors.

  1. Inhibitors of Virus Attachment and Entry:
    • These drugs target either host cell receptors, co-receptors, or viral spike proteins. By inhibiting the attachment and entry of the virus into the host cell, they prevent subsequent steps of the viral replication cycle.
    • Examples include maraviroc, which binds to the CCR5 receptor on host cells, and enfuvirtide, which binds to the gp41 protein on the viral envelope, thereby inhibiting fusion with the host cell membrane.
  2. Uncoating Inhibitors:
    • Drugs such as amantadine prevent the uncoating of the virus, thereby inhibiting the release of the viral genome into the host cell. Amantadine specifically targets the M2 ion channel, preventing acidification and subsequent uncoating of the Influenza A virus.
  3. Inhibition of Viral Replication:
    • Antiviral drugs can target various sites during the replication of viral nucleic acid. DNA or RNA polymerase inhibitors, like acyclovir and tenofovir, prevent DNA/RNA replication.
    • Reverse transcriptase (RT) inhibitors block the synthesis of DNA from RNA. Notably, RT is exclusive to viruses, making these drugs particularly effective. Examples include nucleoside analogs like acyclovir and AZT, which lack a 3’OH group, preventing further nucleic acid synthesis. Non-nucleoside inhibitors, such as nevirapine, bind non-competitively to the polymerase or reverse transcriptase, impairing its function.
  4. Integrase Inhibitors:
    • Drugs like raltegravir inhibit the integration of the viral genome with the host genome, a crucial step for certain viruses.
  5. Interferons:
    • These are proteins produced by virus-infected cells that can inhibit the transcription of viral mRNA. Synthetic interferons are employed as antiviral agents, with their mechanism involving the transformation to triphosphate, subsequently inhibiting viral DNA synthesis.
  6. Viral Protein Synthesis Inhibitors:
    • Some drugs, like formivirsen, utilize an antisense mechanism to inhibit protein synthesis. These short synthetic nucleic acid strands bind to specific mRNA sequences, preventing protein translation.
  7. Inhibitors of Viral Assembly:
    • Protease inhibitors, such as ritonavir, atazanavir, and darunavir, block the proteolytic cleavage of precursor viral proteins, essential for viral assembly.
  8. Inhibitors of Viral Release:
    • Drugs like oseltamivir inhibit the release of newly formed virions from the host cell by targeting enzymes like neuraminidase.

In addition to these direct-acting antivirals, some drugs function as immunomodulators, targeting host-regulated pathways of viral replication. For instance, nitazoxanide amplifies type I interferon pathways, while ivermectin inhibits the nuclear import of both host and viral proteins.

Antiviral medication and its mechanism of action

Antiviral medications are a class of drugs designed to combat viral infections by targeting specific stages of the viral life cycle or the host’s cellular machinery used by the virus. These drugs are crucial in managing and treating infections caused by viruses, especially when vaccines are unavailable. Here, we delve into the mechanisms of action of several antiviral drugs:

  1. Acyclovir:
    • Derived from 2′-deoxiguanosin, Acyclovir becomes active after conversion to acyclovir triphosphate. This compound inhibits viral DNA synthesis by competing with 2′-deoxy guanosin triphosphate for viral DNA polymerase. Once incorporated into the viral DNA, it halts replication. Acyclovir is particularly effective against herpes simplex types 1 and 2, varicella-zoster virus, and certain strains of cytomegalovirus.
  2. Valacyclovir:
    • An oral prodrug of acyclovir, Valacyclovir is converted to acyclovir in the body. It offers better bioavailability than acyclovir and is effective against herpes simplex and varicella-zoster viruses.
  3. Ganciclovir:
    • Structurally similar to acyclovir but with an added hydroxymethyl group. Ganciclovir is activated by a viral encoded phosphotransferase in cells infected with cytomegalovirus. It is particularly effective against cytomegalovirus due to its prolonged intracellular half-life.
  4. Penciclovir and Famciclovir:
    • Penciclovir is structurally similar to ganciclovir but differs in the non-cyclic ribose portion. Famciclovir, its prodrug, is converted to penciclovir in the body. Both are effective against herpes simplex and varicella-zoster viruses.
  5. Foscarnet:
    • An inorganic pyrophosphate analog, Foscarnet directly inhibits viral DNA polymerase by binding to its pyrophosphate binding site. It is effective against cytomegalovirus and acyclovir-resistant herpes simplex virus.
  6. Ribavirin:
    • A guanosine analog, Ribavirin interferes with viral RNA synthesis and has a broad spectrum of activity against RNA viruses. It is particularly effective against dengue and hepatitis C when combined with interferon.
  7. Lamivudine:
    • A pyrimidine nucleoside, Lamivudine inhibits both hepatitis B DNA polymerase and HIV reverse transcriptase. It is used in the treatment of both HIV-1 and HBV infections.
  8. Amantadine and Rimantadine:
    • These compounds inhibit the M2 protein ion channel of the influenza virus, affecting virus release and pH regulation in infected cells. They are effective against influenza virus.
  9. Interferon Alpha:
    • A naturally occurring glycoprotein, Interferon Alpha exerts its antiviral effects by inducing cellular enzymes that inhibit viral protein synthesis. It has shown efficacy against various viruses, including human herpesvirus 8, hepatitis B and C, and papillomavirus.
  10. COVID-19 Specific Antivirals:
  • Remdesivir: Originally developed for Marburg and Ebola viruses, Remdesivir inhibits RNA-dependent RNA polymerase. It has shown potential against SARS-CoV-2 in vitro and in clinical trials.
  • Nitazoxanide: Exhibits broad-spectrum antiviral activity and has shown potential against SARS-CoV-2 in vitro.

Challenges and Side Effects: While antiviral drugs have revolutionized the treatment of viral infections, they are not without challenges. Issues of drug resistance, side effects, and specificity are of concern. For instance, due to the close relationship between host and viral cellular processes, achieving selective toxicity is challenging. Some antivirals can have adverse effects, and the emergence of drug-resistant viral strains remains a significant concern.

Targets of Antiviral Drugs Drugs Mechanisms of Action of Antivirals Applications/Usage
Inhibitors of Viral Attachment/Entry Hydroxychloroquine, Chloroquine (COVID-19), Enfuvirtide, Maraviroc (HIV) Interference with cellular receptor glycosylation, blockage of virus/cell fusion by increasing endosomal pH, direct binding to gp41, and binding to CCR5 of host receptor to block fusion and entry. Used in the treatment of HIV and as a potential treatment for COVID-19.
Uncoating Inhibitors Amantadine, Rimantadine (Influenza) Inhibition of the M2 ion channel, preventing pH-dependent dissociation of viral proteins and subsequent release of nucleic acid into the host cell. Primarily used against Influenza A virus.
Inhibition of Viral Replication Remdesivir, Favipiravir (COVID-19), Foscarnet (HSV), Acyclovir, Ganciclovir (Herpes), Ribavirin (RSV), Dolutegravir, Elvitegravir, Raltegravir (HIV), Zidovudine, Lamivudine (HIV & HBV), Nevirapine, Efavirenz (HIV) Inhibition of RNA-dependent RNA polymerase, DNA polymerase, reverse transcriptase, and integrase. Utilization of nucleoside and non-nucleoside analogs. Used in the treatment of various viral infections including COVID-19, Herpes, RSV, HIV, and HBV.
Viral Protein Synthesis Inhibitors Fomivirsen (CMV), Interferon alfa (HBV, HCV) Antisense therapy that terminates translation and inhibitors that prevent viral protein synthesis, promoting the breakdown of viral components. Used in the management of CMV retinitis and chronic HBV and HCV infections.
Inhibitors of Viral Assembly Ritonavir, Lopinavir (COVID-19), Boceprevir (HCV), Atazanavir (HIV) Inhibition of protease, preventing the cleavage of precursor viral proteins into functional components for viral assembly. Used in the treatment of HIV, HCV, and as a potential treatment for COVID-19.
Inhibitors of Viral Release Oseltamivir (Influenza, COVID-19), Zanamivir (Influenza) Blockage of neuraminidase, preventing the release of new virions from the host cell. Used in the treatment and prophylaxis of Influenza and as a potential treatment for COVID-19.

Additional Information:

  • Applications/Usage: This column provides a brief overview of the typical applications or usage of the antiviral drugs, indicating the viruses they are commonly used to treat.
  • Note: The mechanisms and applications of antiviral drugs can be complex and multifaceted, often involving intricate biochemical pathways and varying efficacy against different viral strains. Furthermore, the usage of some drugs for specific viruses (e.g., Hydroxychloroquine and Chloroquine for COVID-19) may be under research and not yet fully established in clinical practice. Always refer to the most recent clinical guidelines and research for accurate information.

Inhibitors of enzymes associated with virions

Virions, the complete virus particles, utilize a myriad of enzymes to facilitate their replication and propagation within host cells. The inhibition of these enzymes presents a promising avenue for antiviral therapeutics. This article delves into the various substances known to inhibit key enzymes associated with virions.

  1. DNA Polymerases Inhibitors: DNA polymerases are pivotal for the replication of DNA-containing viruses. Several compounds exhibit antiviral activity by targeting these enzymes. Among them, trisodium phosphonoformate (PFA) and trisodium phosphonoacetate (PA) stand out. PFA, in particular, has demonstrated a strong inhibitory effect on herpes simplex virus type I DNA polymerase. The mechanism of action for these inhibitors can range from direct competition with conventional substrates to allosteric modulation.
  2. RNA Polymerases Inhibitors: RNA polymerases play a crucial role in the replication of RNA viruses. Ribavirin triphosphate (RTP), a significant class of molecule, has been identified as a potent inhibitor of RNA polymerase. It particularly disrupts the initial stages of viral RNA synthesis, thereby hindering the replication of the virus.
  3. Deoxypyrimidine Nucleoside Kinase and Thymidine Kinase Inhibitors: These kinases are essential for the activation of certain antiviral drugs. Some thymidine analogues, activated by herpes simplex virus thymidine kinase, have demonstrated antiviral activity. The inhibition of these kinases can be achieved either through direct competition or allosteric modulation.
  4. Viral Neuraminidase Inhibitors: Neuraminidases in influenza viruses are pivotal for the release of progeny virions from infected cells. 2-Deoxy-2,3-dehydro-N-trifluorocetylneuraminic acid has been identified as an inhibitor of influenza virus neuraminidase. By inhibiting this enzyme, the spread of the virus can be curtailed.
  5. mRNA Guanylyl Transferase and mRNA Methyl Transferase Inhibitors: The capping of viral mRNA is a crucial step in the replication of many viruses. RTP has been identified as a potent inhibitor of mRNA guanylyl transferase in certain viruses. Additionally, some compounds can inhibit the methylation of viral mRNA, another crucial step in the replication process.

Inhibitors of the translational processes of viral mRNA

The translation of viral mRNA is a critical step in the life cycle of viruses, allowing them to synthesize the proteins necessary for their replication and propagation. This article delves into the various substances known to inhibit the translational processes of viral mRNA.

  1. mRNA Translation Inhibitors: The translation of certain mRNAs, particularly in the wheat germ system, is inhibited by 7-methylguanosine-5′-monophosphate (m7-GMP). Interestingly, the presence of the 7-methyl group or other methyl groups on guanosine nucleotides can significantly alter their translation inhibitory properties. This suggests the existence of specific recognition sites that interact with these modified nucleotides.
  2. Early Viral Polypeptide Chain Inhibitors: Parafluorophenylalanine (pFPhe) is a compound that has been shown to possess broad-spectrum antiviral activity against both RNA and DNA viruses. Its mechanism of action involves substituting for the amino acid phenylalanine during protein synthesis, leading to the production of non-functional viral peptides.
  3. Inhibitors of Viral DNA Synthesis: Several compounds inhibit the synthesis of viral DNA either by directly blocking the polymerase or by interfering with the template or primer binding. For instance, the incorporation of 5-ldU into viral DNA in place of thymine can lead to DNA instability and distortion. Additionally, various halogenated deoxypyrimidine nucleosides can be incorporated into DNA, potentially leading to non-functional genetic material.
  4. Inhibitors of Non-Viral Enzymatic Processes Involved in DNA Synthesis: Certain antiviral agents target enzymes involved in DNA synthesis, such as thymidylate synthetase. Many deoxyuridine derivatives have been shown to inhibit TMP synthesis. Intercalating agents, which insert between DNA base pairs, can also disrupt DNA replication. While these agents can be effective antivirals, they may also affect cellular DNA replication.
  5. Inhibitors of Viral Glycoprotein Biosynthesis and Assembly: Both DNA and RNA viruses possess membranes with integrated glycoproteins essential for their function. For instance, influenza viruses have hemagglutinin spikes, crucial for viral attachment to host cells. Another component, neuraminidase, is also present on the viral surface and plays a role in viral release. Targeting the biosynthesis or assembly of these glycoproteins offers a potential antiviral strategy.

Development of Antiviral Drugs and Associated Challenges

The control and mitigation of viral diseases have historically relied on public health measures and vaccination campaigns. While these strategies have been effective in curbing the spread of many viral infections, they are not infallible. For certain life-threatening or severe viral diseases, the development and deployment of antiviral drugs become imperative.

The journey of antiviral drug development witnessed its first significant success with the introduction of acyclovir in the 1970s, targeting HSV-1, HSV-2, and VZV. The subsequent HIV-AIDS epidemic catalyzed the expansion of antiviral drug research, leading to the development of drugs against opportunistic pathogens like HIV and CMV. Advances in our understanding of viral genetics, molecular biology, enzymology, and protein structures have paved the way for more sophisticated and efficacious antiviral strategies.

Today, antiviral drugs play a pivotal role in public health, not only alleviating suffering but also saving countless lives. A testament to their success is the transformation of HIV from a fatal disease to a manageable chronic condition, provided patients adhere to antiretroviral therapy. However, an effective host immune response remains crucial for recovery from viral diseases.

Despite these successes, the development of antiviral drugs is fraught with challenges:

  1. Selective Toxicity: Achieving selective toxicity is a significant hurdle. Many compounds can inhibit viruses in tissue culture, but their therapeutic application in humans is limited due to potential harm to host cells. The intrinsic challenge lies in the fact that viruses reside within host cells, making it difficult to target the virus without affecting the host. While the repertoire of safe antiviral drugs is expanding, it remains limited compared to antibacterial agents.
  2. Latency: Some viruses can integrate their nucleic acid into the host genome, remaining dormant and not causing any immediate harm—a state known as latency. When these latent viruses reactivate, they pose therapeutic challenges. Current antiviral drugs primarily target actively replicating viruses, and latent viruses can resume replication once the drug is withdrawn.
  3. Species Variation: Viruses causing similar symptoms, especially respiratory viruses, can belong to different species, complicating diagnosis and treatment.
  4. Antiviral Drug Resistance: The emergence of drug-resistant viral strains is a growing concern. Often, minor nucleotide changes can confer resistance by leading to critical amino acid substitutions in target proteins, altering the virus’s structure and function. The rapid replication cycles of viruses, coupled with their high mutation rates, facilitate the emergence of drug-resistant mutants. The larger the viral population, the higher the likelihood of resistant variants emerging.

Quiz

  1. Kausar S, Said Khan F, Ishaq Mujeeb Ur Rehman M, Akram M, Riaz M, Rasool G, Hamid Khan A, Saleem I, Shamim S, Malik A. A review: Mechanism of action of antiviral drugs. Int J Immunopathol Pharmacol. 2021 Jan-Dec;35:20587384211002621. doi: 10.1177/20587384211002621. PMID: 33726557; PMCID: PMC7975490.
  2. Mechanism of Action of Antiviral Drugs
  3. Kausar, S., Khan, F.S., Rehman, M.I.M.U., Akram, M., Riaz, M., Rasool, G., Khan, A.H., Saleem, I., Shamim, S., & Malik, A. (2021). A review: Mechanism of action of antiviral drugs. International Journal of Immunopathology and Pharmacology, 35, 20587384211002621.
  4. Alsafi, R., Alghamdi, S., & Asif, M. (2022). Antiviral Drugs and Their Roles in the Treatment of Coronavirus Infection. In Antiviral Drugs: Intervention Strategies [Working Title]. IntechOpen.
  5. Vardanyan, R.S., & Hruby, V.J. (2006). Antiviral Drugs. In Synthesis of Essential Drugs.
  6. Denver et al. (2011). Hugo and Russell’s Pharmaceutical Microbiology (8th ed.). A John Wiley & Sons, Ltd. Publication.
  7. Coen, D.M., & Richman, D.D. (2016). Medical Importance of Antiviral Drugs and Barriers to Their Development: Antiviral Agents. Basic Medical Key. Link

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