Antivirals Lecture Notes

Overview

• Discussing antivirals against HIV, Influenza, Hepatitis, Herpes viruses
• Reference materials available on the website (illustrations, notes)

Antivirals Against HIV

Mechanism

• HIV is a retrovirus: converts RNA to DNA
• Targets immune system, specifically T-helper cells (CD4+)

Entry into Host Cell

• Proteins Involved:
  • gp41, gp120 on HIV
  • CD4, CCR5, CXCR4 on T-helper cells
• Fusion and entry inhibitors target these proteins
• Drugs:
  • Enfuvirtide: inhibits interaction of gp41 and CD4
  • Maraviroc: prevents gp120 from binding to CCR5 receptor (not all T-helper cells express CCR5)

Reverse Transcriptase Inhibitors

• NRTIs (Nucleoside Reverse Transcriptase Inhibitors): fake nucleotides incorporated into the growing DNA strand, preventing further elongation
  • Examples: Zidovudine, Abacavir, Lamivudine, Emtricitabine, Stavudine, Tenofovir, Didanosine
• NNRTIs (Non-nucleoside Reverse Transcriptase Inhibitors): bind to allosteric site of reverse transcriptase, altering its function
  • Examples: Nevirapine, Efavirenz, Etravirine, Delavirdine

Integrase Inhibitors

• Prevent integration of viral DNA into host DNA
• Examples: Dolutegravir, Raltegravir, Elvitegravir

Protease Inhibitors

• Block HIV protease enzyme, preventing maturation of viral particles
• Examples: Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir, Saquinavir, Tipranavir

Combination Therapy

• HAART (Highly Active Antiretroviral Therapy)
  • Typically: 2 NRTIs + 1 NNRTI/Integrase inhibitor/Protease inhibitor
• Adjuncts (added in resistant cases): Enfuvirtide, Maraviroc

Antivirals Against Influenza

Mechanism and Stages

1. Entry and Uncoating: proton ion channel (M2)
   • Drug: Amantadine (used primarily for Influenza A)
2. RNA Transcription: endonuclease enzyme
   • Drug: Baloxavir (used for Influenza A & B, <48 hours of symptom onset)
3. Release from Host Cell: neuraminidase enzyme
   • Drugs: Oseltamivir, Zanamivir (used for Influenza A & B, <48 hours of symptom onset)

Adverse Effects

• Amantadine: ataxia, prolonged QT interval, livido reticularis

Antivirals Against Hepatitis

Hepatitis B

• Reverse Transcriptase Inhibitors (NRTIs, NtRTIs)
  • Examples: Lamivudine, Entecavir, Tenofovir, Adefovir
• Adverse Effects: Fanconi Syndrome for Tenofovir, Adefovir
• Interferon Alpha: boosts immune system response
  • Increases antiviral peptides, inhibits protein & RNA synthesis, increases MHC-I expression
  • Adverse Effects: teratogenic, pancytopenia

Hepatitis C

• Protease Inhibitors: target NS3/4A, prevents cleaving of polyproteins
  • Examples: Simeprevir, Paritaprevir
• NS5A Inhibitors: target NS5A, prevent RNA replication and viral assembly
  • Examples: Ledipasvir, Velpatasvir, Daclatasvir
• NS5B Inhibitors: target NS5B (RNA-dependent RNA polymerase)
  • Examples: Sofosbuvir
• Ribavirin: inhibits inosine 5-phosphate dehydrogenase, preventing RNA synthesis
  • Adverse Effects: hemolytic anemia, teratogenic
• Therapy regimen varies by genotype

Antivirals Against Herpes Viruses

• Viral DNA Polymerase Inhibitors (Cidofovir, Foscarnet) for resistant HSV/CMV
  • Adverse Effects: nephrotoxicity, crystal-induced nephropathy (Cidofovir); electrolyte abnormalities, seizures (Foscarnet)
• Guanosine Analogs (Acyclovir, Valacyclovir, Ganciclovir)
  • Indications: HSV, VZV (Acyclovir/Valacyclovir); CMV (Ganciclovir)
  • Mechanism: mimic nucleotides, terminate DNA synthesis
  • Adverse Effects: nephrotoxicity (Acyclovir), pancytopenia (Ganciclovir)

Summary of Adverse Effects

HIV Drugs

• NRTIs: mitochondrial toxicity, pancreatitis, nephrotoxicity (Tenofovir), bone marrow suppression (Zidovudine), hypersensitivity (Abacavir)
• NNRTIs: hepatotoxicity (Efavirenz, Nevirapine), CNS toxicity/dreams (Efavirenz), teratogenic effects (Efavirenz, Delavirdine)
• Integrase Inhibitors: rhabdomyolysis
• Protease Inhibitors: hyperglycemia, lipodystrophy, CYP450 inhibition, nephropathy (Indinavir)

Influenza Drugs

• Amantadine: ataxia, QT prolongation, skin manifestations

Hepatitis Drugs

• Tenofovir, Adefovir: Fanconi Syndrome
• Interferon Alpha: teratogenic, pancytopenia
• Ribavirin: hemolytic anemia, teratogenic

Herpes Drugs

• Cidofovir: nephrotoxicity, crystal-induced nephropathy
• Foscarnet: electrolyte abnormalities, seizures
• Acyclovir: nephrotoxicity
• Ganciclovir: pancytopenia