Steps in viral replication (I)

Transcription

1 Antiviral agents

2 Steps in viral replication (I) Recognition of the target cell Attachment Penetration Uncoating Macromolecular synthesis Assembly of virus Buddding of enveloped viruses Release of virus

3 Viruses treatable with antiviral drugs HSV VZV CMV HIV Influenza A Respiratory syncytial virus (RSV) Hepatitis A, B, and C viruses (HAV;HBV;HCV) Papilloma Picornavirus

4 Agents active against Herpesviruses-I Acyclovir Cidofovir Famciclovir and penciclovir Foscarnet Fomivirsen

5 Agents active against Herpesviruses-II Ganciclovir Valacyclovir Valganciclovir Vidarabine Topical agents: -Trifluridine -Vidarabine

6 Revolution in the field of Infectious diseases: The availability of Increasing number of antiviral agents Against a broadening spectrum of viral pathogens

7 Mechanism of action of antiviral agents is essential, for appropriate clinical use and for understanding and managing antiviral resistance!

8 Acyclovir (acycloguanoside) A class of antiviral agent (nucleoside analog-guanoside analog) Vidarabine was supplanted by acyclovir because of - its ease of administration - low toxicity -efficacy

9 Acyclovir (acycloguanoside) Mechanism of action I: Acyclovir is phosphorylated by HSV and VZVspesific thymidine kinase (TK) Monophospate form

10 Acyclovir (acycloguanoside) Mechanism of action II: Monophospate form cellular enzymes Acyclovir triphospate

11 Acyclovir (acycloguanoside) Mechanism of action II: Acyclovir triphospate -will compete with the natural substrate dgtp for viral DNA polymerase -with its higher affinity -incorporates into newly synthesized viral DNA

12 Acyclovir (acycloguanoside) Mechanism of action IV: Acyclovir triphospate (lacks 3 hydroxyl group necessary to form phosphodiester linkages with incoming nucleotides) incorporated into newly synthesized viral DNA Viral DNA synthesis is terminated

13 Acyclovir resistance Mutation either in viral TK or DNA polymerase genes.

14 Acyclovir Intravenous (i.v.) Oral Topical forms are available.

15 Acyclovir Concentration in cerebrospinal fluid (CSF) is approximately 50% of those in plasma Eliminated by renal excretion Systemic absorpsion after topical application is minimal.

16 Spectrum of activity of acyclovir HSV-1 HSV-2 VZV

17 Acyclovir HSV encephalitis Neonatal HSV infection Primer genital HSV Mucosal and cutaneous HSV-1 and HSV-2 infections in immunocompromised patients VZV infection Recurrent genital herpes

18 Cidofovir Nucleoside analogue Converted intracellularly to its active metobolite by cellular kinases. It does not require phosphorylation to a monophosphate form by viral TK, -that s why it is active against TK- HSV and VZV!!

19 Cidofovir Broad activity: -adenoviruses -herpesviruses -papovaviruses -poxviruses

20 Cidofovir Prophylaxis and treatment of CMV retinitis in patients with AIDS Acyclovir and foscarnet resistent HSV infections

21 Famciclovir and Penciclovir DNA polimerase inhibitor Nucleoside analogue Famciclovir: synthetic Active metobolite: penciclovir 1% topical penciclovir

22 Famciclovir Singles (acute zoster) Genital HSV Mucocutaneous HSV in HIV infected patients

23 Foscarnet Pyrophosphate analogue DNA polymerase inhibitor RT inhibitor Active agains all herpesviruses, HIV, HBV

24 Foscarnet CMV retinitis in AIDS patients Acyclovir resistant mucuccutaneous HSV infections in AIDS patients Gancyclovir resistant CMV pulmoner infections in AIDS patients Acyclovir resistant VZV infections in AIDS patients

25 Fomivirsen Inhibits viral replication by antisense mechanism: its a nucleotide sequence which is complementary to a sequence in mrna transkript and translation is inhibited. Intravitreal injection for CMV retinitis

26 Ganciclovir Guanoside analogue DNA polimerase inhibitor Similar to acyclovir i.v, oral and intraocular application

27 Ganciclovir Mechanism of action I: Ganciclovir is phosphorylated by virus spesific (TK) and CMV spesific phosphoto transferase Monophospate form

28 Ganciclovir Mechanism of action II: Monophospate form cellular kinases Ganciclovir triphosphate

29 Ganciclovir Mechanism of action III: Ganciclovir triphospate -will compete with the natural substrate dgtp for viral DNA polymerase -with its higher affinity -incorporates into newly synthesized viral DNA

30 Ganciclovir Mechanism of action IV: Unlike acyclovir Viral DNA synthesis is not terminated. Viral DNA synthessis continues in CMV infected cells with nuclear accumulation of incomplete noninfectious viral DNA fragments.

31 Ganciclovir Prevention and treatment of CMV retinitis in AIDS patients CMV disease in transplant patients

32 Valacyclovir Active metobolite= acyclovir

33 Vidarabine Nucleosid analogue First licensed systemic antiviral agent Acyclovir has supplanted vidarabine

34 Topical agents for HSV keratitis Trifluridine Vidarabine

35 Interferons Low molecular weight proteins With complex antiviral, immunomodulating, antiproliferative activities. Produced by eucaryotic cells in response to various inducers: viruses 3 types: IFN-a, IFN-β, INF- δ IFN-a2b: widest application

36 HIV(Human immunodeficeincy virus) Nucleoside analogue reverse transcriptase inhibitors:zidovudine (azidothymidine) Non- Nucleoside analogue reverse transcriptase inhibitors Protease inhibitors Integrase inhibitors Gp41 fusion inhibitors CCR5 antagonists

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38 Hepatitis C: Ribavirin + Interferon-a, protease inhibitors Papillomavirus: Interferon-a RSV: Ribavirin CMV:ganciclovir, foscarnet VZV: valacyclovir, famciclovir Picornavirus: pleconaril

39 Anti-influenza drugs 1. Influenza A: Amantadine Rimantadine 2. Influenza A and B Zanamivir: enzyme inhibitors of neurominidase, virus release is inhibited. Oseltamivir: the same The length of disease is reduced if taken within the first 48 hours