Antiviral agents Hamzeh Elayan 2015.

Viruses are made up of core genome of nucleic acid contained in a protein shell called Capsid Surrounded by lipoprotein membrane called envelope (Genome + Capsid + Envelope = Virion) Viruses are obligate intracellular parasite ie. do not have a metabolic machinery of their own – uses host enzymes. Viruses have DNA or RNA, never both. Some viruses have unique enzymes for DNA/RNA synthesis or protein cutting in virus assembly. Most multiplication take place before diagnosis is made

Viral Replication Adsorption to and penetration of susceptible cells. Synthesis of RNA or DNA. Synthesis of early, nonstructural proteins. Synthesis of late, structural proteins Assembly of viral particles and release

General Mechanism of Action Nucleoside Analogues General Mechanism of Action 1.Taken up by cells 2. Converted by viral and cellualr enzymes to the triphosphate form 3. Triphosphate form inhibits: • DNA polymerase • Reverse transcriptase • RNA polymerase 4. Or it may get incorporated into growing DNA leading to abnormal proteins or breakage.

guanine nucleoside analogs Active against Acyclovir (ACV) guanine nucleoside analogs Active against HSV-1 (Labial and ocular infection) HSV-2 (Genital infection) Varicella -zoster infections Epstein barr virus Resistance : HSV and varicella zoster -Deficiency in thymidine kinase activity -Changes in virus directed enzymes

Therapeutic uses of Acyclovir Genital Herpes (HSV–II) Acyclovir 5% ointment. Late & severe cases, orally or Iv infusion (HSV–I) Mucocutaneous : Remains localized to lips and gums (Acyclovir skin cream) H.Simplex encephalitis: IV/8h for 10 days. H. Simplex keratitis: Acyclovir eye ointment. Chickenpox : Oral 400mg TDS for 7 days Herpes zoster infections: Acyclovir less active Adverse Effects: Oral : Headache, nausea, vomiting, diarrhea, vertigo IV : Phlebitis, rash , hypotention Nephrotoxicity

Valacyclovir Valacyclovir is a prodrug of Acyclovir with better bioavailability. A Guanine analogue with antiviral effect for Herpes group only. Inhibits viral DNA polymerase selectively Incorporated into DNA and terminates synthesis Active against HSV-1 (Labial and ocular infection) HSV-2 (Genital infection) Varicella-zoster infections Epstein barr virus

Ganciclovir • Mechanism like Acyclovir • Active against all Herpes viruses including CMV • Low oral bioavailability given I.V. • Drug of choice for Cytomegalovirus (CMV) infections: retinitis, pneumonia, colitis Adverse effects: Bone marrow suppression (leukopenia 40%, thrombocytopenia 20%) CNS effects (headache, behavioral, psychosis, coma, convulsions) 1/3 of patients have to stop because of adverse effects

Adefovir - Adenosine analogue Converted by cellular kinases to active diphosphate - Inhibits Hepatitis B virus DNA polymerase - Gets incorporated into DNA causes Chain termination Use: Chronic hepatitis B Adverse effects: Nephrotoxicity, lactic acidosis, hepatomegaly.

Ribavirin Inhibit replication of both DNA and RNA viruses Triphosphate inhibits RNA polymerase Adverse Effects: Anemia due to hemolysis and bone marrow suppression Uses: Ribavirin is the drug of choice for: • RSV bronchiolitis and pneumonia in hospitalized children (given by aerosol) Ribavirin is an alternative drug for: • Influenza, Para influenza, Measles virus infection in immunocompromised patients

Foscarnet An inorganic pyrophosphate inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase • Blocks binding site of pyrophosphate and inhibits cleavage •Given IV Uses: HSV, VZV, CMV, Epstein barr virus, Hepatitis B and HIV Resistance due to mutations in DNA polymerase gene Adverse Effects: Nephrotoxicity, Hypocalcemia, Anemia Acute tubular necrosis, Crystalluria CNS – tremor, irritability, seizure , hallucinations, Rash, fever, nausea, vomiting

Antiviral therapies for Influenza Viral Uncoating Inhibitors Amantadine Rimantadine • Chemically a tricyclic amine not related to any nucleotide • Inhibit penetration of virus to cells ,the uncoating of certain virus and viral replication. • M2 protein which acts as ion is one of the target. • Prevent diseases caused by influenza A • Treatment of Parkinson’s disease (Amantadine) Adverse effects: • GI upset • Headache • Nervousness • Postural hypotension, ankle edema

Oseltamivir orally (oral bioavalibility 80%) Neuraminidase Inhibitors Inhibit neuraminidase enzyme of influenza which is essential for release of virus Zanamivir inhalation Oseltamivir orally (oral bioavalibility 80%) Therapeutic Use Treatment of acute uncomplicated Influenza A (H1N1 virus, swine flu) Adverse effects N/V, Bronchospasm and abnormal respiratory function

Interferons • Three classes of interferons – α , β, γ • α and β interferons: produced by all the cells in response to viral infections • γ interferon : produced only by T lymphocyte and NK cells in response to cytokines – immune regulating effects • γ has less anti-viral activity compared to α and β interferon

Toxicity: flu-like syndrome, BM suppression; CNS Mechanism of Action Induction of the following enzymes: A protein kinase which inhibits protein synthesis An oligo-adenylate synthase which leads to degradation of viral mRNA A phosphodiesterase which inhibit t-RNA Induction of these enzymes leads to inhibition of translation • Interferon prevent spread of viruses to new cells (Viral hepatitis) • Natural products of the immune system in viral infections • Antiviral, anticancer and immuno-modulating Toxicity: flu-like syndrome, BM suppression; CNS Use: Hepatitis B and C

Entecavir • Guanosine analogue • Competitively inhibits viral DNA polymerase • Approved by FDA in march 2005 for treatment of chronic hepatitis B • Oral bioavailability : 95% • Adverse Effects : Headach, fatigue, NV Peramivir Neuramidase inhibitor • Approved in 2009 For emergency treatment of hospitalised patients of H1N1 infection Used iv for patients resistant to Oseltamivir, zanamivir Peramivir