Antiviral agents
Dr.Israa Omar
Viruses
• They are small infective agents consisting of
nucleic acid (RNA or DNA) enclosed in a
protein coat.
• They are not cells and, having no metabolic
machinery of their own, are obligate
intracellular parasites, utilizing the metabolic
processes of the host cell they infect to
replicate
• DNA viruses usually enter the host cell nucleus
and direct the generation of new viruses.
Viruses
• RNA viruses direct the generation of the new
viruses, usually without involving the host cell
nucleus(the influenza virus is an exception in
that it does involve the host cell nucleus)
• RNA retroviruses(e.g. HIV,T-cell leukaemia
virus)contain an enzyme, reverse
transcriptase, which makes a DNA copy of the
viral RNA. This DNA copy is integrated in to
the host cell genome and directs the
generation of new virus particles.
Antiviral drugs
• Most antiviral drugs generally fall in to the
following groups :
1. Nucleoside analogue that inhibit the viral
reverse transcriptase enzyme, preventing
replication(e.g. Lamivudine, Zidovudine)
2. Non nucleoside analouges that have the same
effect (e.g. Efavirez)
3. Inhibitors of proteases that prevent viral protein
processing( Saquinavir, Indinavir)
Antiviral drugs
4. Inhibitors of viral DNA polymerase that
Prevent replication (e.g. Aciclovir,
Famciclovir)
5. Inhibitors of HIV fusion with host cells
6. Inhibitors of viral capsule disassembly(e.g.
Amanitidine)
7. Inhibitors of neuroaminidase that prevent
viral viral escape from infected cells(e.g.
Oseltamivir).
Antiviral drugs
8. Immuno-modulators that enhance host
defence (e.g. interfrons and inosine
pranobex).
9. Immunoglobulin and related preperations
that contain neutralizining antibodies to
various viruses.
Features of Antiviral Drugs
• Antivirals have a narrow spectrum of action
• Inhibit active replication; do not kill latent
viruses, need host immune response
• Resistance is common
• Synergistic effects when given together
• Efficacy relates to con. in infected cells
• Start therapy early for optimal efficacy
Sites Of Anti Viral Drug Action
Enfuvirtide, maraviroc
Reltegravir
Oseltamivir
Indinavir
1. Neucleoside reverse transcriptase
inhibitors (NRTIS)
• Zidovudine Inhibit reverse transcriptase –
prevent conversion of viral RNA to DNA
• All NRTIs are nucleoside analogs e.g. Zidovudine
(azidothymidine- AZT) is a thymidine analog
• NRTIs: Narrow therapeutic window, dose limiting
toxicities (mainly due to mitochondrial toxicity
and inhibition of cellular DNA polymerases)
• In toxicity– withdraw drug until symptoms clear
or become tolerable OR the drug has to be
discontinued
• Used mainly for treatment of HIV.
1.Neucleoside reverse transcriptase
inhibitors (NRTIS)
• Resistance to zidovudine:
• Major cause of treatment failure
•  Likelihood of resistance:
 duration of therapy
Advancing disease
• Due to point mutations in reverse transcriptase
enzyme
• 33% patients on monotherapy with AZT become
resistant within a year
1.Neucleoside reverse transcriptase
inhibitors (NRTIS)
• Lamivudine: Inhibit HIV- reverse-transcriptase
by competing with dCTP & Inhibits HBV-DNA
polymerase
• Uses:
1. Chronic Hepatitis B infection
with evidence of active viral replication
• 2. HIV infection
SE: N/V, headache, insomnia, fatigue
2. Non nucleoside reverse
transcriptase inhibitors (NNRTIS)
• Nevirapine, Delavirdine and Efavirenz
• MOA: Bind directly to reverse transcriptase
• Allosteric inhibition of enzyme function
• Blocks transcription of viral RNA to DNA
• Note: They are NOT pro drugs!
• Toxicity: Relatively low toxicity, also effect lipid
profile
Toxicities do not overlap with NRTIs
Major toxicity:Skin rashes
3. Protease inhibitors
• Saquinavir, Indinavir and Ritonavir
• In HIV and many other viral infection, mRNA is
translated in to biochemichally inert poly
proteins .
• Virus-specific protease converts the
polyprotiens in to various structural and
functional protiens by cleavage at approirate
position .
3. Protease inhibitors
• Toxicity of PI
• Saquinavir: GIT disturbances
• Indinavir: “trunkal obesity”, Nephrolithiasis
(kidney stones) and Hemolytic anemia
• Ritonavir: Paresthesia
4. DNA polymerase inhibitors
• Aciclovir, Ganciclovir, Foscarnet and Ribavirin
• Compete with dGTP for viral DNA- polymerase
& inhibit viral DNA synthesis
• 1st two are purine analogs
• Acyclovir and Ganciclovir are prodrugs
• Foscarnet acts directly on DNA polymerase
ACYCLOVIR: Guanine analog
MOA: Inhibits HSV replication
Acyclovir
Viral thymidine kinase
Acyclo-MP
Cell kinase
Acyclo-DP
Cell kinase
Acyclo-TP
(ACTIVE DRUG)
Competes with
dGTP for viral
polymerase
Stops viral replication
Chain termination
Incorporated into
growing DNA strand
•
•
•
•
•
4. DNA polymerase
inhibitors(aciclovir)
Uses of acyclovir:
Genital Herpes
Orolabial herpes
Herpes encephalitis: Acyclovir I/V
Varicella zoster:Oral, till all lesions
encrusted , I/V in disseminated CNS or Visceral
infection
• Cytomegalovirus: Prophylaxis only (prevent
CMV infection in transplant patients)
• Use in pregnancy: for 1st episode of genital H. to
prevent neonatal herpes (H.pneumonia)
4. DNA polymerase
inhibitors(aciclovir)
• Side effects: NEPHROTOXIC
(reversible crystalline nephropathy)
Encephalopathy (rare)
Resistance:Mutations occur in the thymidine
kinase gene causing an enzyme that does not
phosphorylate acyclovir
• Occurs more in HIV+ive people
4. DNA polymerase inhibitors(Ganciclovir)
• 1st drug effective against CMV
• Uses: Cytomegalovirus (CMV):
• Acute infection (retinitis, pneumonia in
AIDS)
• Prophylactic (in transplant patients, AIDS)
• S/E: Bone marrow toxicity
(granulocytopenia & thrombocytopenia)
• Drug Interactions:
DO NOT give with ZIDOVUDINE (overlapping
myelosuppression toxicities)
4. DNA polymerase inhibitors(Foscarnet)
• (alternate to Ganciclovir for CMV)
• Uses: CMV infections and Acyclovir-resistant
HSV encephalitis
• MOA: Directly inhibits DNA polymerase
• S. Effect: reduce Renal function,
hypocalcaemia, teratogenic, mutagenic &
carcinogenic drug
Drug Interactions:
Cyclosporine (renal toxicity), Pentamidine
(hypocalcaemia), Imipenem (seizures)
4. DNA polymerase inhibitors(Ribavirin)
• MOA: Synthetic analogue of nucleoside; inhibits
GTP synthesis & , inhibits 5̀ capping of viral mRNA,
RNA-dependant RNA polymerase
S/ E: Headache, insomnia, anemia, teratogenesis
Uses: Severe RSV infection with serious
underlying respiratory, CV problems or immuno
compromised
C.I: Pregnancy
• Wide spectrum antivirus against many DNA and
RNA viruses like RSV, hepatitis C virus as well as
Lassa virus
5. Inhibitors of HIV fusion with host
cells
• Enfuvirtide: Prevents the fusion of HIV with
the host cell membrane
• Uses: To treat AIDS which is progressing
despite HAART
• Unwanted adverse effect include flu like
symptoms, headache and mood disturbance
6. Inhibitors of viral capsule
disassembly(Amanitidine)
• MOA: effectively block M2 ion channels, thus
inhibiting viral disassembly.
• Uses: it is active against Influenza A but has no
action on influenza B
• S/E: CNS: insomnia & restlessness
Livedo reticularis
•  dose in renal dysfunction
• Good alternative to a vaccine in the elderly or in
immuno compromised patients
7. Inhibitors of neuroaminidase
Oseltamivir: Tamiflu
• Flu virus attaches to host cell membrane –
hemagglutinin on viral envelope binds to sialic
acid moiety in glycoprotein of cell membranes
• Neuraminidase enzyme cleaves viral attachment
• Neuraminidase inhibitor keep the virus tethered
to the host cell membrane; prevent it from being
released and thus spreading to other cells
• Prophylaxis and treatment of Influenza A and B
8. Immuno-modulators
• Immuno-modulators are drugs that act by
moderating the immune response to viruses
or use immune mechanism to target a virus or
other mechanism.
8. Immuno-modulators(Interferon)
• INFs are produced by B and T lymphocyte,
macrophages and fibroblasts in response to
the presence of viruses and cytokines .
• The INFs bind to specific ganglioside receptors
on the host cell ribosomes, the production of
enzymes, that inhibit translation of viral
messenger RNA in to viral proteins, thus
halting viral replication. They have a broad
spectrum of action and inhibit the replication
of most viruses in vitro.
8. Immuno-modulators(Interferon)
• INF-α2a used clinically for treatment of Hep C.
• There are reports that INFs can prevent
reactivation of herps simplex after trigeminal
root section and can prevent spread of
herpses zoster in cancer patient .
• Preparation of INFs conjugated with
polyethylene glycol(pegylated INFs) have
longer lifetime in the circulation
• S/E: Many, Flu-like ,syndrome, Bone marrow
suppression and alopecia.
8. Immuno-modulators(Inosine Pranobex)
• It may interfere with viral nucleic acid
synthesis but also has immuno-potentiating
actions on the host.
• It is sometimes used to treat herpes infections
in mucosal tissues or on the skin.
9. Immunoglobulin and related
preperations
• The antibodies are directed against the virus
envelope and can neutralize some viruses and
prevent their attachment to the host cell.
• If used early before the onset of sign and
symptoms, it may attenuate or prevent
measles, infectious hepatitis, German measls,
Rabies and poliomyelities
9. Immunoglobulin and related
preperations
• Palivisumab :related in terms of its
mechanism to immunoglobulins .
• It is a monoclonal antibody directed against
glycoprotien on the surface of RSV.
• It is used by IM injection to prevent the
infection by this virus in the infant.
Thank you