antiviral agents - opencourses.emu.edu.tr
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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