Antiviral agents
I.Viruses –biology
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obligate intracellular parasites
consist of a core genome in a protein shell and some are surrounded by a lipoprotein
lack a cell wall and cell membrane
do not carry out metabolic processes
replication depends on the host cell machinery
 Steps for Viral Replication
1) adsorption and penetration into cell
2) uncoating of viral nucleic acid
3) synthesis of regulatory proteins
4) synthesis of RNA or DNA
5) synthesis of structural proteins
6) assembly of viral particles
7) release from host cell
II.Pharmacology of antiviral agents
1. Antiherpesvirus agents
Mechanism of action - the dGTP analog and is incorporated into DNA and causes DNA chain
termination; the terminated chain inhibits viral DNA polymerase.
Antiherpesvirus agents - spectrum
• Herpesviruses – ACYCLOVIR, CIDOFOVIR, FAMCYCLOVIR, FOSCARNET,
GANCYCLOVIR, IDOXOURIDINE, TRIFLURIDINE
• CMV – GANCYCLOVIR, FOMIVIRSEN, FOSCARNET, TRIFLURIDINE,
CIDOFOVIR
Therapeutic use
Acyclovir – HSV: genital HSV infections, primary herpetic gingivostomatitis, herpes labialis,
mucocutaneous HSV infection in immunocompromised patients, VZV: varicella
Gancyclovir – CMV infections
Foscarnet – CMV and HSV infection in gancyclovir-resistant and acyclovir-resistant patients
Cidofovir – CMV retinitis, HSV: acyclovir-resistant mucocutaneous HIV infection, others:
adenovirus disease in transplant recipients, molluscum contagiosum in HIV patient
Famciclovir – HSV and VZV infections
Idoxouridine – HSV keratitis, herpes labialis, genitalis and zoster
Trifluridine – HSV keratoconjuctivitis and keratitis
Adverse effects
• Acyclovir
• Foscarnet
• Ganciclovir
• Cidofovir
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- GI, rashes, neurotoxiciy, nephrotoxicity
- Nephrotoxicity, hypocalcemia
- Myelosupression
- Nephrotoxicity, ypersensitivity
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2. Antiretroviral agents
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Nucleoside RT (reverse transcriptase) inhibitors
Non-nucleoside RT inhibitors
HIV protease inhibitors
Fusion inhibitors
Entry inhibitors
Integrase inhibitors
 Nucleoside RT inhibitors ZIDOVUDINE, STAVUDINE, LAMIVUDINE,
DIDANOSINE, ABACAVIR, TENOFOVIR, ZALCITABINE, EMTRICITABE
Adverse effects
• Zidovudine - anemia, granulocytopenia, malaise, myalgia, nausea, insomnia,
hyperpigmentation, lactic acidosis-steatosis syndrome
• Didianosine - neuropathy, pancreatitis, diarrhea
• Zalcitabine - nephropathy
• Lamivudine - well tolerated
• Abacavir
- hypersensistivity
• Tenofovir
- well tolerated, flatulence
• Emtricitabine - well tolerated, skin hyperpigmentation
 Non-nucleoside RT inhibitors
 NEVIRAPINE
 EFAVIRENZE
 DELAVIRDINE
 Adverse effects
 Rashes,sedation, hepatotoxicity
 HIV protease inhibitors
• SAQUINAVIR, RITONAVIR, INDINAVIR, NELFINAVIR, AMPRENAVIR,
LOPINAVIR, ATAZANAVIR
• Active against HIV-1 and HIV-2
• Mechanism: inhibit protease which is responsible for cleaving precursor molecules
necessary to produce final structural proteins of the virion core
• Adverse effects: altered body fat distribution, insulin resistance, dyslipidemia, liver
function impairement, GI symptoms, nephrolithiasis (Indinavir), skin rashes
 Fusion inhibitors
ENFUVIRTIDE
Blocks gp 41 subunit
of the viral envelope glycoprotein – involved in fusion
Active: against HV-1
Adverse effects: injection-site reactions
 Entry inhibitors
MARAVIROC
Inhibitor of CCRT coreceptor
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 Integrase inhibitors
RALTEGRAVIR
Integrase action
1. A complex is formed between integrase and the viral DNA
2. The integrase removes nucleotides from the 3' ends of the DNA duplex by endonucleolytic
cleavage
3. The viral DNA becomes covalently linked to the host chromosome through a strandtransfer reaction, also catalyzed by integrase
3. Antiinfluenza Agents
 Cyclic amines
AMANTADINE , RIMANTADINE
 inhibit the uncoating of viral RNA (Block M2 protein) therefore inhibiting replication
 resistance due to
 mutations in the RNA sequence coding for the structural M2 protein
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Neuraminidase inhibitors
ZANAMIVIR, OSELTAMTVIR
Active against influenza virus A and B
Mechanism: inhibit neuraminidase which is an essential viral glycoprotein for replication and
release
Adverse effects: well tolerated
Therapeutic use: uncomplicated influenza infection, given intranasally (z) or orally (o)
4. Anti-hepatitis agents
Lamivudine -Nucleoside Reverse Transcriptase Inhibitor
Adefovir -Nucleotide Inhibitor
Interferon Alfa
Pegylated Interferon Alfa
Ribavirin
 Interferon
Intracellular effects
1. Transcription inhibition (inhibits Mx protein and mRNA synthesis)
2. Translation inhibition: activated 2’-5’-oligoadenylate [2-5(A)] synthetase– vRNA cleaved, protein kinase
- intiation of mRNA inhibited, phosphodiesterase – tRNA function blocked
3. Proteins posttranslational modyfication - glycosylation of proteins inhibited
4. Inhibition of virus maturation – glycoproteins maturation inhibited, changes in membrane – budding
inhibited
Spectrum - Most of viruses except few of DNA types
Interferon - pharmacokinetics
• parenerally only, given 3-times weekly, pegIFN (polyethylene glycol) once a week, steady-state
levels 5-8 weeks after initiation of weekly dosing, eliminated by the liver and/or kidneys (end-stage
renal disease)
Therapeutic uses:
• Chronic hepatitis type C and B
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Genital warts
Kaposi sarcoma-HIV-related
Hairy leukemia and other malignancies
Multiple sclerosis
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Adverse effects
• Influenza-like symptoms
• Bone marrow depression
• Autoimmune effects: hypothyreosis
• Neurotoxicity: somnolence confusion, behavioral disturbances, neurasthenia, depression
• Hair loss
• Nephritis
• Cardio, - hepatotoxicity
• Impaired fertility
 Ribavirin
• Mechanism of action: intracellulary phosphorylated
• Inhibits inosine-5’-dehydrogenase – synthesis of GTP
• Inhibits GTP-dependent 5’capping of viral mRNA
• Inhibits influenza virus transcriptase
• Enhances viral mutagenesis – lethal mutagenesis
Summary: multiple sites of action
• Spectrum: Influenza and parainfuenza viruses, RSV, HCV, adenoviruses, paramyxoviruses,
arenaviruses, bunyaviruses, flaviviruses
• Therapeutic use: chronic HCV infection, RSV bronchiolitis and RSV pneumonia in children
(aerosol), in immunocompromised patients, occasionaly – influenza, vaccinia, parainfuenza, measles,
Lassa fever, SARS, Congo hemorrhagic fever
• Adverse effects: irritation, wheezing, anemia (hemolysis and bone marrow depression), nausea,
insomnia, depression, embryotoxic, teratogenic and oncogenic (cat. X)
 Adefovir
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Spectrum – HBV
Adefovir dipivoxil – inhibits DNA polymerase and reverse transcriptases, serves as chain terminator
Adverse effects: nephrotoxicity, diarrhea, hepatitis exacerbation, genotoxic, embryotoxic
Therapeutic use: chronic HBV infections
5. Imiquimod
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Topical treatment of condylomata acuminata (genital and perisanal warts)
Induces cytokines with antivirial and immunomodulatory effects
Skin irritations
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