15.1 Classes of antiviral drugs and their mechanisms of action

Antiviral drugs are crucial weapons against viral infections. They target different stages of the viral life cycle, from entry to replication and release. Understanding their mechanisms helps us develop better treatments and combat drug resistance.

Classes of antivirals include nucleic acid synthesis inhibitors, protein processing blockers, and entry inhibitors. Each class works differently, like stopping viral DNA replication or preventing virus release. Knowing these differences is key to effective treatment strategies.

Antiviral Drug Classes and Targets

Nucleic Acid Synthesis Inhibitors

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• Nucleoside/nucleotide analogs target viral DNA or RNA polymerases inhibiting viral genome replication
  • Incorporate into growing viral nucleic acid chain causing chain termination or mutations
  • Examples include acyclovir (herpes viruses) and ribavirin (respiratory syncytial virus, hepatitis C)
• Polymerase inhibitors directly interfere with viral RNA or DNA polymerases preventing viral genome replication
  • Act as nucleoside analogs or allosteric inhibitors disrupting polymerase function
  • Examples include sofosbuvir (hepatitis C) and remdesivir (SARS-CoV-2)

Protein Processing and Function Inhibitors

• Protease inhibitors interfere with viral protease enzymes preventing the cleavage of viral polyproteins into functional proteins
  • Bind to active site of viral proteases blocking polyprotein processing
  • Examples include lopinavir (HIV) and simeprevir (hepatitis C)
• Neuraminidase inhibitors target the neuraminidase enzyme of influenza viruses inhibiting viral release from infected cells
  • Mimic sialic acid blocking enzyme activity and preventing virion release
  • Examples include oseltamivir and zanamivir (influenza A and B)

Retrovirus-Specific Inhibitors

• Reverse transcriptase inhibitors specifically target the reverse transcriptase enzyme of retroviruses blocking the conversion of viral RNA to DNA
  • Nucleoside or non-nucleoside based incorporating into DNA chain or allosterically inhibiting enzyme
  • Examples include zidovudine (AZT) and efavirenz (HIV)
• Integrase inhibitors block the integration of viral DNA into the host cell genome primarily used against retroviruses like HIV
  • Bind to active site of integrase enzyme preventing viral DNA insertion
  • Examples include raltegravir and dolutegravir (HIV)

Entry and Fusion Inhibitors

• Entry inhibitors prevent viral attachment fusion or entry into host cells by targeting viral envelope proteins or host cell receptors
  • Block receptor binding prevent membrane fusion or inhibit conformational changes for viral entry
  • Examples include enfuvirtide (HIV) and maraviroc (HIV CCR5 antagonist)

Mechanisms of Antiviral Action

Competitive Inhibition and Substrate Mimicry

• Nucleoside/nucleotide analogs act as competitive inhibitors incorporating into growing viral nucleic acid chain
  • Cause chain termination or induce mutations in viral genome
  • Structurally similar to natural nucleosides but lack 3' hydroxyl group for chain extension
• Neuraminidase inhibitors mimic sialic acid the natural substrate of neuraminidase blocking enzyme's activity
  • Prevent release of newly formed virus particles from infected cells
  • Bind to active site with higher affinity than natural substrate

Enzyme Active Site Binding

• Protease inhibitors bind to active site of viral proteases preventing cleavage of viral polyproteins
  • Block formation of functional structural and enzymatic components
  • Often designed to mimic transition state of protease-substrate complex
• Integrase inhibitors bind to active site of integrase enzyme preventing insertion of viral DNA into host genome
  • Interfere with strand transfer step of integration process
  • Stabilize integrase-viral DNA complex preventing interaction with host DNA

Allosteric Inhibition

• Non-nucleoside reverse transcriptase inhibitors allosterically inhibit enzyme function
  • Bind to site distant from active site inducing conformational changes
  • Reduce enzyme flexibility and catalytic activity
• Some polymerase inhibitors act as allosteric inhibitors altering enzyme conformation
  • Bind to sites outside the catalytic center affecting polymerase function
  • May interfere with protein-protein interactions or substrate binding

Antiviral Interference with Replication

Targeting Specific Replication Stages

• Entry inhibitors prevent initial steps of infection blocking viral attachment fusion or entry
  • Halt replication cycle before it begins in host cell
  • Examples include fusion inhibitors (enfuvirtide) and receptor antagonists (maraviroc)
• Reverse transcriptase and integrase inhibitors interfere with early post-entry steps in retrovirus replication
  • Prevent establishment of proviral DNA in host genome
  • Critical for blocking retroviral life cycle (HIV)

Disrupting Genome Replication and Protein Processing

• Nucleoside/nucleotide analogs and polymerase inhibitors disrupt genome replication
  • Interfere with synthesis of new viral DNA or RNA
  • Can induce lethal mutagenesis or premature chain termination
• Protease inhibitors act during late stages of viral replication cycle
  • Prevent maturation of viral proteins necessary for assembly of infectious particles
  • Result in production of non-infectious viral particles

Blocking Virus Release and Spread

• Neuraminidase inhibitors interfere with final stage of influenza virus replication
  • Prevent release of newly formed virions from infected cells
  • Reduce viral spread to neighboring cells
• Targeting different stages of viral replication cycle effectively reduces viral load
  • Limits spread of infection within host
  • Combination therapy targets multiple stages simultaneously

Efficacy and Limitations of Antiviral Drugs

Broad-Spectrum vs. Virus-Specific Antivirals

• Nucleoside/nucleotide analogs effective against broad range of viruses
  • May have significant toxicity due to effects on host cell metabolism
  • Examples include acyclovir (herpes viruses) and ribavirin (multiple RNA viruses)
• Entry inhibitors can be highly specific but may have limited efficacy against established infections
  • Often strain-specific due to viral envelope protein variability
  • Maraviroc only effective against CCR5-tropic HIV strains

Resistance Development and Combination Therapy

• Protease inhibitors highly effective against HIV and hepatitis C virus (HCV)
  • Rapid development of drug resistance if used as monotherapy
  • Necessitates use in combination with other antivirals
• Reverse transcriptase inhibitors crucial in HIV treatment
  • Require combination therapy to prevent emergence of resistant viral strains
  • Part of highly active antiretroviral therapy (HAART) regimens

Timing and Administration Considerations

• Neuraminidase inhibitors effective against influenza viruses
  • Must be administered early in course of infection for optimal results
  • Prophylactic use during outbreaks can reduce transmission
• Efficacy limited by factors such as drug resistance toxicity and drug-drug interactions
  • Genetic variability of viruses contributes to resistance development
  • Host factors (metabolism immune status) affect drug efficacy

Emerging Antiviral Strategies

• Integrase inhibitors show high efficacy against HIV with high genetic barrier to resistance
  • Use limited to retroviruses currently
  • Potential for development against other viruses with similar enzymes
• Polymerase inhibitors can be highly effective with high genetic barrier to resistance
  • Development challenging due to conserved nature of viral polymerases
  • Successful examples include sofosbuvir (HCV) and remdesivir (SARS-CoV-2)