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

3. 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

5. 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

6. 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)

7. 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

8. 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

9. 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

10. 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

11. 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

14. 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.

15. 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

16. 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

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

18. Neuroamidase Inhibitors

21. 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.

22. 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.

23. 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

25. Sialic Acid
Oseltamivir
Zanamivir
Sialic Acid

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

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

29. Deoxycytidine Monophosphate
Pencyclovir
Famicyclovir
Cidofovir
Cidofovir
Deoxycytidine Monophosphate

30. 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

33. 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

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

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

37. 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

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

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

40. Abcavir A
Guanosine Analogue

41. Stavudine s

42. Zalcitabine Z

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

45. Non-nucleoside reverse transcriptase Inhibitors

48. Protease inhibitors

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

50. 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

51. 3-Deazaneplanocine A
Inhibits
s-adenosylhomocysteine hydrolase

52. 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

53. 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

54. Thanks
Thanks