(13) Anti-Virals

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key concepts

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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: viral envelope
Replicate intra-cellularly by utilizing host cell machinery
Intracellular mode of replication reduces the number of potential targets for antiviral drug therapy
Current antiviral drugs exploit differences between the structures and functions of viral and human proteins to achieve selectivity of antiviral action

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Steps for Viral Replication

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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

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Inhibition of viral attachment and entry

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Enfuviritide: Anti-HIV peptide,firstt drug that acts by inhibiting viral entry to be approved by FDA.
Similar to gp41
Binding of HIV to its cellular receptors triggers a conformational change in gp41 that exposes the fusion-active segment. The drug prevents this process.

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Inhibition of viral uncoating

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Amantidine and Rimantidine
Exclusively against influenza A virus, inhibit uncoating of viral RNA.
Amantidine blocks the proton channel M2 of the virus particle.
Commonly used for treatment and prophylaxis of influenza A virus.
Amantidine also used in Parkinsonism (dopaminergic).
Rimantidine has less CNS adverse effects and used commonly.

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Antiherpes agents

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Acyclovir - prototype
Ganciclovir
Foscarnet

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Acyclovir and valacyclovir (prodrug, better availability)‏

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A guanine analogue with antiviral activity for Herpes group only

Acyclovir----thymidine kinase-->acycloGMP---.cellular kinases---.acycloGTP

AcycloGTP Inhibits viral DNA polymerase selectively and is
Incorporated into DNA and terminates synthesis


Resistance:
1. ↓ activity of thymidine kinase
2. altered DNA polymerase

Toxicity:
1. Encephalopathy
2. Renal Insuficiency


Use:
1. H. simplez I and II
2. H. zoster and Varicella,
not good for CMV

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Ganciclovir

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Mechanism like acyclovir
Active against all Herpes viruses including CMV
Low oral bioavailability given I.V.
Most common adverse effect: bone marrow suppression (leukopenia 40%, thrombocytopenia 20%) and CNS effects (headache, behavioral, psychosis, coma, convulsions).
1/3 of patients have to stop because of adverse effects
Drug of choice for CMV infections: retinitis, pneumonia, colitis.

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Foscarnet

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An analog of inorganic pyrophosphate
Active against Herpes (I, II, Varicella, CMV), including those resistant to acyclovir and ganciclovir.
Direct inhibition of DNA and RNA polymerase and HIV RT
Nephrotoxicity (25%) most common adverse effect
Hypocalcemia (chelates divalent cations)‏
Others: hypokalemia, hypomagnesemia
Use: CMV retinitis and other CMV infections instead of ganciclovir. H. simplex resistant to acyclovir. HIV.

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Classes of antiretroviral drugs

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Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI's): zidovudine, lamivudune
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI's): nevirapine, efavirenz
Protease Inhibitors (PI's): ritonavir ,indinavir, lopinavir, nelfinavir, saquinavir
Fusion inhibitors: enfuvirtide

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Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI's)‏

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Abacavir
Emtricitabine (FTC)
Zidovudine (AZT)
Didanosine (DDI)
Zalcitabine (DDC)
Lamivudine (3TC)
Tenofovir (disoproxil fumarate)‏
Stavudine (D4T)

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Effects of antiretroviral therapy

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Total eradication of HIV infection can not be achieved with currently available antiretroviral regimens
Treatment goals:
1. maximal and durable suppression of viral load
2. restoration and / or preservation of immunologic function
3. improvement of quality of life,
4. reduction of HIV-related morbidity and mortality.

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HAART

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HAART (Highly Active Antiretroviral Therapy) - available since 1995
Triple or quadruple therapy, e.g.:
Efavirenz (NNRTI) + zidovudine (NRTI) + lamivudine (NRTI)‏
efavirenz + tenofovir (NRTI) + emtricitabine (NRTI)‏
lopinavir (PI) boosted with ritonavir (PI) + zidovudine + lamivudine
lopinavir boosted with ritonavir + tenofovir + emtricitabine.

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Anti-retroviral agents

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Zidovudine (AZT)‏
First anti-HIV drug (1987)‏
Cellular enzymes phosphorylate to the triphosphate form which inhibits RT and causes chain termination
Adverse effect:
Granulocytopenia and anemia: 45% in AIDS but 5% if asymptomatic HIV
Severe headache, nausea, insomnia, myalgias
Decreased mortality and opportunistic infections, weight gain, better quality of life, delays signs and symptoms of AIDS

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Other retroviral RT inhibitors

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Other nucleoside analogs: didanosine, stavudine, zalcitabine: same as AZT but can cause peripheral neuropathy and pancreatitis. Can be used with AZT for enhanced effect and less toxicity.
Non-nucleoside RT inhibitors: e.g. neviparine. Noncompetitive binding to RT and direct inhibition at a site different from AZT and others. May be active against AZT-resistant strains. Can be used in combination. Main adverse effect is rash.

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Protease inhibitors

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Produce non-infectious particles or virions
Reduces the number of new rounds of infection in susceptible cells
To be effective must be prolonged, profound and constant.
Pharmacokinetics important to maintain constant concentrations within the effective range.
Metabolic adverse effects (DM, hyperglycemia, hypercholesterolemia) and GI (diarrhea, pain vomiting).

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Inhibition of viral release

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Zanamivir and oseltamivir
Inhibit enzyme neuraminidase, expressed by influenza virus and needed for release of virus from the infected cells: virus remains tethered and cannot spread to other cells.
Zanamivir has poor oral bioavailability: must be inhaled, oseltamivir 75% BA, oral.
Active against both influenza A & B viruses.

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Other drugs: interferons

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Interferon alpha, beta and gamma
Interferon alpha & beta have antiviral & antiproliferative effects, interferon gamma mainly immunomodulator.

Several sites of action in viral cycle but mainly inhibit translation of viral proteins.
Toxicity: flu-like syndrome, BM suppression; CNS side effects
Interferon alpha: Hepatitis B and C, genital warts

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Newer anti-viral drugs

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Fomivirsen: New anti-CMV drug designed to be antisense oligonucleotide which target specific RNAs – IE2, a gene regulatory protein of CMV. Given intravitreally.
Ribavirin: broad spectrum anti-viral. FDA approved in aerosol form for severe respiratory syncytial virus (RSV) and in combination with interferon for chronic hepatitis C.
Palivizumab: mAb against RSV
Imiquimod: immunomodulator with unknown mechanism. Topical for genital and anal warts: condyloma acuminata, molluscum contagiosum. Also some skin cancers.

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Summary of anti-virals

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Anti-herpes drugs: acyclovir, foscarnet, ganciclovir- Mechanism and adverse effects. Drugs used specifically for CMV: ganciclovir
Anti-retroviral drugs: zidovudine as prototype, mechanism and adverse effects, protease inhibitors side effects
Nevirapine induced skin rash.
Amantidine and rimantidine : used in influenza A virus and Parkinsonism.
Ribavirin is effective against Hepatitis C and RSV.
Zanamivir and oseltamivir inhibit neuraminidase enzyme and effective against both influenza A and B.