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Virus Structure

• Viruses are small, infectious agents that contain nucleic acid (RNA or DNA) enclosed in a protein coat.
• Viruses are not cells and lack their own metabolic machinery.
• Viruses are obligate intracellular parasites, which means they use the host cell's metabolic processes to replicate.
• DNA viruses typically enter the host cell nucleus to direct the production of new viruses.
• RNA viruses generally direct the generation of new viruses without entering the host cell nucleus. The influenza virus is an exception and does involve the host cell nucleus.
• RNA retroviruses, like HIV and T-cell leukemia virus, contain reverse transcriptase.
• Reverse transcriptase makes a DNA copy of the viral RNA, which integrates into the host cell genome.
• Once integrated, the viral DNA directs the creation of new virus particles.

Virus Classification

• Examples of RNA viruses include Hepatitis A, C, D, and E viruses, influenza A, B, and C viruses, coronaviruses, poliovirus, rabies virus, and measles, mumps, and rubella viruses.
• Examples of DNA viruses include Hepatitis B virus, herpes virus, human papilloma virus, smallpox, monkeypox, and adenovirus.

Virus Life Cycle

• Attachment: The virus binds to the host cell.
• Uncoating: The virus releases its genetic material into the host cell.
• Replication: The viral genome is replicated and viral proteins are produced.
• Translation: Viral mRNA is translated into proteins.
• Processing: Viral proteins are processed and modified.
• Assembly: New virus particles are assembled.
• Release: New viruses are released from the host cell.

Classification of Antiviral Drugs

• Drugs target HIV
• Drugs target Herpes viruses
• Drugs target Hepatitis viruses including Anti-HCV and Anti-HBV drugs
• Drugs target Respiratory Viruses including Influenza, Respiratory syncytial virus and SARS COV-2

Drugs to Treat HIV Infection (Antiretroviral Drugs)

• Attachment (Fusion) Inhibitors
• Reverse Transcriptase Inhibitors (RTIs)
• Integrase Inhibitors
• Protease Inhibitors

Attachment (Fusion) Inhibitors

• Enfuvirtide and Maraviroc are examples.
• Enfuvirtide inhibits HIV-1 by competing with the gp41 subunit of the viral envelope and preventing fusion with the host cell membrane CD4 receptors.
• It specifically interferes with the gp41 subunit of HIV-1.
• Its adverse effects include pain and erythema at the injection site.
• Maraviroc operates by binding to the CCR5 receptor on the host cell membrane.
• Interrupts the attachment of the gp120 subunit of HIV-1
• Necessary for attachment of gp120 subunits of HIV virus.

Reverse Transcriptase Inhibitors (RTIs)

• Nucleoside analogs (NRTIs): Zidovudine, lamivudine, and tenofovir.
• NRTIs compete with normal physiological nucleosides used for DNA synthesis.
• Differ from normal substrates by a minor modification in the sugar (ribose) molecule.
• Act as "false building blocks," incorporating themselves into the DNA and preventing synthesis because normal bridges can no longer be built to build the double strand.
• NRTIs prevent the development of functional viral DNA.
• Zidovudine can cause myopathy and anemia, while tenofovir may cause acute tubular necrosis.
• Non-nucleoside analogs (NNRTIs): Efavirenz and nevirapine.
• NNRTIs attach directly to reverse transcriptase.
• The enzyme with NNRTI cannot function normally.
• Production of viral DNA from RNA is blocked.
• NNRTIs prevent the virus from converting RNA into DNA and infecting the cell.
• Nevirapine may cause rash and hepatitis.

Integrase Inhibitors

• Raltegravir and elvitegravir are examples.
• These inhibit the viral enzyme integrase to prevent HIV replication and viral integration into the host cell.
• GIT-related adverse effects such as nausea and diarrhea.

Protease Inhibitors

• Ritonavir, lopinavir, and atazanavir are examples.
• An infected cell produces large viral proteins (polyproteins).
• Protease cleaves polyproteins into enzymes & structural proteins for the new virus.
• Protease inhibitors attach to and block protease enzyme.
• The resultant virus particles are defective and inactive.
• Metabolic side effects such as diabetes, hypertriglyceridemia, and hypercholesterolemia are potential adverse effects.
• Ritonavir is a potent inhibitor of CYP450.

Drugs Used to Treat HCV infection

• Treatment depends on the viral genotype, and this should be tested prior to treatment.
• There are 6 major genotypes of HCV.
• Genotype 1 is most prevalent in the USA.
• Genotype 4 is most prevalent in the Middle East.
• Achieve sustained virological response (SVR), defined as undetectable serum HCV RNA six months after the end of therapy.
• Genotypes 2 and 3: SVR can be achieved after 24 weeks and have better responses to treatment.
• Genotypes 1 and 4: Therapy continues for 48 weeks and has a lower response rate.
• Hepatitis C management rapidly advances with clearance rates of ~ 95%.
• Interferon-based treatments are no longer recommended.

NS5A Inhibitors

• Daclatasvir and ledipasvir are examples.
• NS5A is essential for viral replication and assembly.

NS5B Inhibitors

• Sofosbuvir and dasabuvir are examples.
• NS5B is essential RNA polymerase enzyme for viral replication.

Protease Inhibitors

• Glacaprevir and semiprevir are examples.
• Inhibit NS3/4A protease enzyme.
• Essential for posttranslation processing of viral protein.
• Concomitant use with amiodarone increases risks of bradycardia and heart block.

Drugs Used to Treat HBV Infection

• Antiviral therapy is normally only for chronic HBV and not for all patients.
• Indications for treatment are abnormal LFTs + HBV DNA >2000IU/mL, acute liver failure, decompensated cirrhosis, and hepatocellular carcinoma.
• Treatment options include lamivudine, tenofovir (which inhibit HIV reverse transcriptase and HBV DNA polymerase), entecavir (which inhibits only HBV DNA), ribavirin, and interferon alpha.

Ribavirin

• Suppresses RNA polymerase activity in a wide range of both RNA and DNA viruses.
• Used for respiratory viruses (respiratory syncytial and influenza), HCV, and HBV.
• Now limited, more selective drugs are available.
• Adverse effects include dose-dependent hemolytic anemia and is genotoxic for sperm and ovum.
• It is contraindicated in men and women attempting conception and for up to 6 months after cessation of TTT.

Interferon Alpha (IFN-a)

• Interferons are cytokines that responds to viral infection and tumors.
• Three major types: iFN-α, iFN-B, iFN-y
  • iFN-α: Produced by many cell types, has major antiviral effect.
  • iFN-B: Produced by many cell types.
  • iFN-y: Produced by T-lymphocytes.
• Short half-life.
• Linked to polyethylene glycol (PEG) to extend its duration of action.
• Synthesized by recombinant DNA tech & administered by S.C. injection.
• Affects viral replication.
• Stimulates apoptosis of viral infected cells.
• Regulates immune response.
• Therapeutic uses include chronic HBV & HCV infection (IFN-alpha), treatment of some cancers, such as hairy cell leukemia (IFN-α), and treatment of multiple sclerosis (IFN-beta).
• Therapeutic uses for chronic HBV & HCV infection (IFN-alpha) are limited by low efficacy & high adverse effects.
• Cannot be used in decompensated liver, as it worsens hepatic decompensation.
• Adverse effects include immune disturbance, fatigue, flu-like symptoms, neurotoxicity, anemia and bone marrow depression.

Drugs Used to Treat Herpes Virus

• Herpes virus drugs include Acyclovir and Gancyclovir.

DNA Polymerase Inhibitors

• All three drugs (Acyclovir, Ganciclovir, Famciclovir) are purine analogs.
• They are activated inside the infected cells by the viral enzyme thymidine kinase (TK) to the active nucleotide form.
• After activation, they incorporate into viral DNA.
• Inhibits viral DNA replication.
• Acyclovir is activated by HSV-1 and 2.
• Ganciclovir is activatedby TK of CMV.
• Famciclovir is activatedby TK of VZV.

Acyclovir

• Purine analog
• Inhibits the activity of viral DNA polymerase.
• A guanosine analog, monophosphorylated in the cell by the herpes virus-encoded enzyme thymidine kinase.
• Virus-infected cells are most susceptible.
• The monophosphate analog is converted to the di- and triphosphate forms by host cell kinases.
• Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase, which is incorporated into the viral DNA, causing premature DNA chain termination.
• Herpes simplex virus (HSV) types I and II, Epstein-Barr virus, Varicella-zoster virus, Cytomegalo virus (CMV).
• Well tolerated, but can cause nausea, diarrhea, and headache.
• May cause nephrotoxicity & neurotoxicity (reversible) if given by IV infusion.

Ganciclovir

• Similar to acyclovir only, active against CMV.
• Treatment of choice for CMV and CMV retinitis.
• Adverse effects are neutropenia (reversible) and thrombocytopenia.

Drugs Used to Treat Influenza Virus

Inhibitors of Uncoating

• Amantadine and rimantadine.
• They bind to the M2 protein (the proton channels) of the virus to inhibit virus uncoating.
• Active against influenza A virus only.
• Neuropsychiatric disturbances especially in old age.
• Mottled skin pattern because blood flow through the arterioles that supply cutaneous capillaries causes reticulated purple discoloration.

Inhibitors of Release

• Oseltamivir and Zanamivir.

• Inhibit viral neuraminidase for viral budding and release.

• Active against influenza A and B.

• ---navir (protease inhibitor for HIV)

• ---previr (protease inhibitor of HCV)

• ----tegravir (integrase inhibitor for HIV)

• ----asvir (NS5A inhibitor for HCV)

• ----buvir (NS5B inhibitor for HCV)

• ----mivir (release inhibitor for influenza virus)

• -----tadine (uncoating inhibitor for influenza virus)

• Attachment inhibitor only for HIV

• Integrase inhibitor only for HIV

• Uncoating inhibitor only for Influenza virus

• Release inhibitors only for influenza virus

Principal Classes of Antiviral Drugs and Some Common Therapeutic Uses

Principal Common Unwanted Effects of Some Antiviral Drugs