Antiviral Agents and Mechanisms

Objectives

• Identify potential drug targets in viral infections
• List antiviral agents for human viral infections (HIV, HSV, respiratory and hepatic viral infections)
• For each drug:
  • Explain its mechanism of action
  • Describe clinically-relevant pharmacokinetics
  • Identify major adverse effects

Viral Structure and Replication

• Viruses are not cells; they lack cell walls and membranes
• Viruses utilize the host cell's metabolic processes
• Symptoms often appear when most viral particles have replicated

Rise of Antivirals

• Number of approved antiviral drugs has increased over time, particularly since the 1980s
• Research into viral replication and better understanding of viruses drives development of new drugs

Points of Attack

• Block viral binding or entry to host cells
• Prevent viruses from making new RNA copies
• Interfere with the production of proteins required to form new viruses

Antiretroviral Therapy for HIV Infection

• Averts millions of HIV/AIDS deaths through treatment
• Prolongs life expectancy by years
• Decreases transmission risk

Antiretroviral Therapy Classification

• Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Protease inhibitors
• Integrase strand transfer inhibitors (INSTIs)
• Chemokine receptor antagonists
• Fusion inhibitors

Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Chemically diverse compounds that bind near the catalytic site of reverse transcriptase
• Efavirenz (oral) is an example
• Potential adverse effects include skin rash, gastrointestinal disturbances, and vivid dreams

Effect on CYP450 Enzymes

• Some antivirals are potent inhibitors of CYP2B6
• This can lead to drug accumulation, potentially causing increased toxicity
• Important to consider drug-drug interactions

Enzyme Inhibition and Induction

• Some antiviral drugs inhibit drug metabolism, resulting in drug accumulation
• Some antivirals induce the expression of drug metabolism enzymes, leading to decreased drug effectiveness

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

• Prodrugs activated by host cell phosphorylation
• Lack a 3'-hydroxyl group
• Incorporated into growing DNA chains, triggering premature chain termination
• Examples include Zidovudine and Tenofovir

Adverse Effects

• La ctic acidosis, hepato-steatosis, and lipodystrophy are potential adverse effects of some antiretroviral therapies.
• Mitochondrial DNA polymerase inhibition can cause toxicity

Protease Inhibitors

• Inhibit viral proteases, preventing the maturation of viral proteins into infectious virions
• Atazanavir, Boceprevir, and Daclatasvir are examples

Adverse Drug Reactions

• Fat redistribution (buffalo hump, abdominal fat accumulation, limb wasting) can occur with some antivirals

Integrase Strand Transfer Inhibitors (INSTIs)

• Inhibit viral DNA insertion into host genome
• Reduced bioavailability when taken with antacids

Entry Inhibitors/CCR5 Antagonists

• Block CCR5 coreceptor to prevent HIV entry
• Effective only for R5 strains
• Maraviroc is an example

Fusion Inhibitors

• Block the conformational change of gp41 to prevent HIV membrane fusion with CD4 cell membrane
• Enfuvirtide is an example

Treatment of Herpes Virus Infections

• Acyclovir (oral, IV, topical)

Treatment of Respiratory Viral Infections

• Influenza A and B, respiratory syncytial virus, SARS-CoV-2, COVID-19

Neuraminidase Inhibitors

• Oseltamivir (prodrug), activated by metabolic processes
• Inhibits viral neuraminidase enzyme
• Prevents release of new virions and prevents spread

Endonuclease Inhibitors

• Baloxavir, Favipiravir
• Inhibit endonuclease activity to prevent viral gene transcription and replication

Ribavirin

• Synthetic guanosine analog which inhibits RNA and DNA replication for various RNA and DNA viruses (RSV, Hep-C)
• Contraindicated in pregnancy

Treatment of Hepatic Viral Infections

• Hepatitis B and Hepatitis C

Treatment of Hepatitis B

• Interferons, usually with NRTIs
• Pegylated forms last longer

Hepatitis C Treatment Strategy

• Improved response to direct-acting antivirals (DAAs)
• Effective in different genotypes

Direct-Acting Antivirals

• Target different parts of the HCV polyprotein
• Prevent replication and assembly
• Examples include Glecaprevir, Ledipasvir, Sofosbuvir
• Drug-drug interactions with CYP450 enzymes need consideration

This quiz focuses on identifying potential drug targets in viral infections, particularly for common human viral infections like HIV and HSV. You'll explore various antiviral agents, their mechanisms of action, pharmacokinetics, and major adverse effects. Test your knowledge on the rise of antiviral therapies and their points of attack against viruses.