Antiviral Agents Mr. Sachin Shinde S. M. Joshi College Hadapsar, Pune Assistant Professor S. M. Joshi College Hadapsar, Pune

General Characteristics of Viruses Viruses are obligate intracellular parasites they cannot reproduce outside a living cell Viruses do not contain an ATP-generating system Viruses do not contain any protein synthesizing machinery

Virion Structure envelope (if present) The virion or virus particle consists of: nucleic acid (RNA or DNA) surrounded by a protein coat – Capsid envelope (if present) Originates from the host cell’s membrane The capsid (for animal viruses) comes in 2 basic shapes: icosahedral - many-faced, spherical shape helical - tube of protein

Some virions also contain essential enzymes or other proteins Reverse transcriptase in HIV The capsid or the envelope has special attachment proteins or glycoproteins that mediate the attachment of the virus to the target cell Virus Attachment Proteins (VAP)

Viral Replication How viruses affect the cells they infect depends on the virus and the host cell Some viruses will immediately begin producing new virions if the new virions are released by the cell breaking open, the cell dies (most naked viruses) some virions can leave the cell without killing it (most enveloped viruses) Other viruses will insert their DNA into the host chromosome and cause a latent infection

Viral Replication Contains six steps: Attachment – VAPs attach to cell receptors This determines the virus host range and tissue tropism Epstein-Barr virus~C3d on human B-cells rhinovirus~ICAM-1 of epithelial tissue HIV~CD4 on helper T-cells Influenza virus~sialic acid on epithelial cells rabies virus~acetylcholine receptors on neurons

Viral Replication Penetration - this occurs by: Receptor-mediated endocytosis (most naked viruses) Viropexis – naked viruses slip directly through the membrane Membrane fusion – enveloped viruses Uncoating - the capsid is lost, exposing the DNA or RNA

Viral Replication Macromolecular synthesis of Viral Proteins and Nucleic Acids Retroviruses are especially complex these are RNA viruses that convert their RNA into DNA the enzyme reverse transcriptase is responsible for this conversion the DNA is then incorporated into the host cell’s genome the viral DNA is then transcribed and translated to produce more virions

Viral Replication Assembly – once all the necessary proteins and nucleic acids are synthesized, They automatically assemble into new virions This happens in the cytoplasm or nucleus in naked viruses It happens at the membrane for enveloped viruses Release – the virions exit the cell Cell lysis or exocytosis for naked viruses Budding for enveloped viruses

Antiviral Agents Agents that disrupt virus attachment to host cell receptors, penetration or uncoating. Agents inhibiting viral enzymes. Inhibitors of Viral Transcription Inhibitors of Viral Translation Agents that interfere with viral regulatory proteins Agents that interfere with viral assembly.

Anti-influenza Agents Amantadine · Oseltamivir · Peramivir · Rimantadine · Zanamivir Anti-herpesvirus agents   Aciclovir · Cidofovir · Docosanol · Famciclovir · Foscarnet · Fomivirsen · Ganciclovir · Idoxuridine · Penciclovir · Trifluridine · Tromantadine · Valaciclovir · Valganciclovir · Vidarabine Antiretroviral Agents  NRTIs Zidovudine · Didanosine · Stavudine · Zalcitabine · Lamivudine · Abacavir · Tenofovir NNTI’s Nevirapine · Efavirenz · Delavirdine PIsSaquinavir · Indinavir · Atazanavir · Ritonavir · Nelfinavir · Amprenavir · Lopinavir · Tipranavir Other antiviral agents Fomivirsen · Enfuvirtide · Imiquimod · Interferon · Ribavirin · Viramidine

Agents inhibiting Virus Attachment, Penetration and early Viral Replication Amantadine Inhibits Penetration of RNA virus. Inhibits uncoating of viral genome Well absorbed orally Effective against Influenza A virus

Rimantadine More effective than amantadine Inhibits viral uncoating Low CNS toxicity with increased metabolism

Neuroamidase Inhibitors

What is Sialic Acid? Sialic acid-rich oligosaccharides on the glycoconjugates found on surface membranes help keep water at the surface of cells. The sialic acid-rich regions contribute to creating a negative charge on the cells surface. Since water is a polar molecule, it has a partial positive charge on both hydrogen molecules, it is attracted to cell surfaces and membranes. This also contribues to cellular fluid uptake.

It seems that the Hemagluttinin subtypes in avian influenza strains bind preferentially to a2,3 linked sialic acid residues, while the human influenza isolates prefer a2,6 linked sialic acid residues.

What is neuraminidase? Neuraminidase has functions that aid in the efficiency of virus release from cells. Neuraminidase cleaves terminal sialic acid residues from carbohydrate moieties on the surfaces of infected cells. This promotes the release of progeny viruses from infected cells. Neuraminidase also cleaves sialic acid residues from viral proteins, preventing aggregation of viruses. Inhibiting neuraminidase slows the release of the virus from the host cell and commercial drugs target this enzyme

Sialic Acid Oseltamivir Zanamivir Sialic Acid

So it is logical that the inhibitors were designed to be sp2 hybridized ‘flat’ at the carbon adjacent to the CO2H group

Inhibitors of Viral DNA Polymerase Acyclovir Valacyclovir R = H, Gancyclovir R = H, Gancyclovir R = Val, Valgancyclovir Descyclovir

Deoxycytidine Monophosphate Pencyclovir Famicyclovir Cidofovir Cidofovir Deoxycytidine Monophosphate

Mechanism of Action : inhibit DNA polymerase activity. Trifluridine Vidarbine Idoxuridine Mechanism of Action : inhibit DNA polymerase activity. -- Activated intracellularly by host enzymes to the triphosphate form. • Note: Can affect host DNA polymerases leading to bone marrow toxicity. Therapeutics : used against Herpes Simplex Viruses (HSV). -- Primarily indicated for treatment of Keratitis (in eye drops). Side effects/Toxicities: Local hypersensitivity Vidarbine

Resistance to acyclovir mutations in viral TK gene alter affinity for drug or just completely inactivate the gene viral DNA polymerase mutations reduce recognition of phosphorylated drug as substrate for DNA synthesis

Antiviral Therapy against HIV Nucleoside analog reverse-transcriptase inhibitors (NARTIs or NRTIs) Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) Protease Inhibitors

Nucleoside analog reverse-transcriptase inhibitors Zidovudine Lamivudine Didanosine Abacavir Stavudine Zalcitabine

Zidovudine Azidithymidine(AZT) mechanism selective reverse transcriptase inhibitor pharmacokinetics: orally active, penetrates CSF toxicity: bone marrow depression (anemia, leukopenia) headache, nausea, myopathy, anorexia, fatigue therapeutic effects: increase CD4+ T cells partially restoring immune system reverses AIDS dementia resistance: major problem RTase mutations

Lamivudine similar to zidovudine resistance develops quickly: selects for met184val mutation in RTase lamivudine + zidovudine combination dramatically slows resistance development

Didanosine D Base is inosine Enzymatic reactions convert it into 2’-3’-Dodoxyadenosine trophosphate which is activve form.

Abcavir A Guanosine Analogue

Stavudine s

Zalcitabine Z

Adefovir dipivoxil R = H, R’ = CMe3 Tenofovir R = Me, R’ = OCHMe2

Non-nucleoside reverse transcriptase Inhibitors

Protease inhibitors

Broad Spectrum Antiviral Agents Ribavirin Cyclopentenyl Cytosine 3-Deazaneplanocine 3-Deazaneplanocine

Cyclopentenyl Cytosine Inhibits cytidine triphosphate synthetase. Blocks the synthesis of cytidine triphosphate which is the buildind block for RNA synthesis Blocks the synthesis of mRNA

3-Deazaneplanocine A Inhibits s-adenosylhomocysteine hydrolase

Ribavirin (Virazole) It is phosphorylated by adenosine kinase. Inhibits Viral specific RNA polymerase Disrupts mRNA Inhibits Nucleic acid synthesis Inhibits Guanyl transferase and prevents 5’ capping of mRNA

Interferons Small natural proteins produced by host cell in response to foreign invaders Inhibit Protein Synthesis Inhibit Viral replication Immunomodulators can be used to induce interferon production. E. g. avridine Various interferons are named after their source α- Interferon - Lymphocytes β –Interferons – Fibroblasts γ- Interferons – T Cells

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