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 Indinavir Oseltamivir Reltegravir

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 Acyclo-MP Acyclo-DP Acyclo-TP (ACTIVE DRUG) Viral thymidine kinase Cell kinase Incorporated into growing DNA strand Chain termination Stops viral replication Competes with dGTP for viral polymerase

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.

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