Antiviral agents

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

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

Agents active against

Herpesviruses-I

Acyclovir

Cidofovir

Famciclovir and penciclovir

Foscarnet

Fomivirsen

Agents active against

Herpesviruses-II

Ganciclovir

Valacyclovir

Valganciclovir

Vidarabine

Topical agents: -Trifluridine

-Vidarabine

Revolution in the field of Infectious

diseases:

The availability of

Increasing number of antiviral agents

Against a broadening spectrum of viral

pathogens

Mechanism of action of antiviral

agents

is essential ,

for appropriate clinical use and

for understanding and managing antiviral

resistance !

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

Acyclovir

(acycloguanoside)

Mechanism of action I:

Acyclovir is phosphorylated by

HSV and VZV-

spesific thymidine

kinase (TK)

Monophospate form

Acyclovir

(acycloguanoside)

Mechanism of action II:

Monophospate form

cellular

enzymes

Acyclovir triphospate

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

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

Acyclovir resistance

Mutation

either in viral TK or

DNA polymerase genes.

Acyclovir

Intravenous (i.v.)

Oral

Topical forms are available.

Acyclovir

Concentration in cerebrospinal fluid (CSF)

is approximately 50% of those in plasma

Eliminated by renal excretion

Systemic absorpsion after topical

application is minimal.

Spectrum of activity of acyclovir

HSV-1

HSV-2

VZV

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

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!!

Cidofovir

Broad activity:

-adenoviruses

-herpesviruses

-papovaviruses

-poxviruses

Cidofovir

Prophylaxis and treatment of CMV

retinitis in patients with AIDS

Acyclovir and foscarnet resistent HSV

infections

Famciclovir and Penciclovir

DNA polimerase inhibitor

Nucleoside analogue

Famciclovir: synthetic

Active metobolite: penciclovir

1% topical penciclovir

Famciclovir

Shingles (acute zoster)

Genital HSV

Mucocutaneous HSV in HIV infected

patients

Foscarnet

Pyrophosphate analogue

DNA polymerase inhibitor

RT inhibitor

Active agains all herpesviruses, HIV, HBV

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

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

Ganciclovir

Guanoside analogue

DNA polimerase inhibitor

Similar to acyclovir

i.v, oral and intraocular application

Ganciclovir

Mechanism of action I:

Ganciclovir is phosphorylated by

virus spesific(TK) and CMV

spesific phosphoto

transferase

Monophospate form

Ganciclovir

Mechanism of action II:

Monophospate form

cellular

kinases

Ganciclovir triphosphate

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

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.

Ganciclovir

Prevention and treatment of

CMV retinitis in AIDS patients

CMV disease in transplant patients

Valacyclovir

Active metobolite= acyclovir

Vidarabine

Nucleosid analogue

First licensed systemic antiviral agent

Acyclovir has supplanted vidarabine

Topical agents for HSV keratitis

Trifluridine

Vidarabine

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

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

Hepatitis C: Ribavirin + Interferon-a,

protease inhibitors

Papillomavirus: Interferon-a

RSV: Ribavirin

CMV:ganciclovir, foscarnet

VZV: valacyclovir, famciclovir

Picornavirus: pleconaril

Anti-influenza drugs

1. Influenza A:

Amantadine Resistance

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