Mode of Action of Antiviral Drugs

A. Treatment of Hepatic Virus Infections

  • The hepatitis viruses are classified into 5 types (A, B, C, D, and E), each have a pathogenesis specifically involving replication in and destruction of hepatocytes.
  • Of this group, hepatitis B and hepatitis C are the most common causes of chronic hepatitis, cirrhosis, and hepatocellular carcinoma and are the only hepatic viral infections for which therapy is currently available.
  • Oral therapy includes lamivudine, adefovir, entecavir, tenofovir, or
  • Combination therapy of an interferon plus lamivudine is no more effective than monotherapy with lamivudine.
  • In the treatment of chronic hepatitis C, the preferred treatment is the combination of peginterferon-α-2a or peginterferon-α-2b plus ribavirin, which is more effective than the combination of standard interferons and ribavirin.

1. Interferon

  • Interferon is a family of naturally occurring, inducible glycoproteins that interfere with the ability of viruses to infect cells.
  • The antiviral mechanism is incompletely understood.
  • It appears to involve the induction of host cell enzymes that inhibit viral RNA translation, ultimately leading to the degradation of viral mRNA and tRNA.

2. Lamivudine

  • Lamivudine is cytosine analog and is an inhibitor of both hepatitis B virus (HBV) DNA polymerase and human immunodeficiency virus (HIV) reverse transcriptase.
  • Lamivudine must be phosphorylated by host cellular enzymes to the triphosphate (active) form.
  • This compound competitively inhibits HBV DNA polymerase at concentrations that have negligible effects on host DNA polymerase.

3. Adefovir

  • Adefovir dipivoxil is a nucleotide analog that is phosphorylated to adefovir diphosphate , which is then incorporated into viral DNA.
  • This leads to termination of further DNA synthesis and prevents viral replication.

4. Entecavir

  • Entecavir is a guanosine analog approved for the treatment of HBV infections.
  • Following intracellular phosphorylation to the triphosphate, it competes with the natural substrate, deoxyguanosine triphosphate, for viral reverse transcriptase.
  • Entecavir has been shown to be effective against lamivudine-resistant strains of HBV.

5. Telbivudine

  • Telbivudine is a thymidine analog that can be used in the treatment of HBV.
  • Unlike lamivudine and adefovir, telbivudine is not active against HIV or other viruses.
  • The drug is phosphorylated intracellularly to the triphosphate, which can either compete with endogenous thymidine triphosphate for incorporation into DNA or else be incorporated into viral DNA, where it serves to terminate further elongation of the DNA chain.

B. Treatment of Herpes Virus Infections

  • Herpes viruses are associated with a broad spectrum of diseases, for example, cold sores, viral encephalitis, and genital infections.
  • The drugs that are eff ective against these viruses exert their actions during the acute phase of viral infections and are without effect during the latent phase.
  • Except for foscarnet and fomivirsen, all are purine or pyrimidine analogs that inhibit viral DNA synthesis.

1. Acyclovir

  • Acyclovir (acycloguanosine) is the prototypic antiherpetic therapeutic agent.
  • It has a greater specificity than vidarabine against herpesviruses.
  • Herpes simplex virus (HSV) Types 1 and 2, varicella- zoster virus (VZV), and some Epstein-Barr virus–mediated infections are sensitive to acyclovir.
  • Acyclovir, a guanosine analog that lacks a true sugar moiety, is monophosphorylated in the cell by the herpes virus–encoded enzyme, thymidine kinase.
  • Therefore, virus-infected cells are most susceptible.
  • The monophosphate analog is converted to the di- and triphosphate forms by the host cells with the action of cellular kinases.
  • Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase and is itself incorporated into the viral DNA, causing premature DNA-chain termination.
  • Irreversible binding of the acyclovir-containing template primer to viral DNA polymerase inactivates the enzyme.

2. Ganciclovir

  • It is an analog of acyclovir and is active against herpes viruses including herpes simplex, Herpes zooster, Epstein Barr virus and cytomegalovirus(CMV).
  • It is the analogue of guanosine.
  • The first phosphorylation in a cell is carried out by a virus enzyme, protein kinase.
  • Ganciclovir is more likely to become incorporated in cell DNA and inhibits viral DNA polymerase.
  • Ganciclovir has a lower Selectivity Index (SI) than acyclovir and can cause significant side-effects, especially reduced numbers of blood cells because of damage to bone marrow cells.

3. Cidofovir

  • Cidofovir is approved for treatment of CMV-induced retinitis in patients with AIDS.
  • Cidofovir is a nucleotide analog of cytosine, the phosphorylation of which is not dependent on viral enzymes.
  • It inhibits viral DNA synthesis.

4. Fomivirsen

  • Fomivirsen is an antisense oligonucleotide directed against CMV mRNA.
  • Its use is limited to those who cannot tolerate or have failed other therapies for CMV retinitis.

5. Foscarnet

  • Unlike most of the antiviral agents, foscarnet is not a purine or pyrimidine analog.
  • Instead, it is a phosphonoformate (a pyrophosphate derivative) and does not require activation by viral (or human) kinases.
  • It is a simple straight chain phosphonate, unrelated to any nucleic acid precursor, which inhibits viral reverse transcriptase and DNA polymerase.
  • It is active against Herpes simplex, CMV and HIV.

6. Vidarabine

  • Vidarabine is one of the most effective of the nucleoside analogs.
  • It is adenine arabinoside and the first drug which could be used i.v. for life threatening Herpes simplex virus infection.
  • It is an adenine analog and after phosphorylation inhibits DNA polymerase and inhibits viral DNA synthesis.

7. Idoxuridine

  • Idoxuridine is 5-iodo-2-deoxyuridine (IUDR) and acts as thymidine analogue.
  • It was first pyrimidine antimetabolite to be used as antiviral drug.
  • It competes with thymidine, gets incorporated in DNA so that faulty DNA is formed which breaks down easily.
  • This DNA directs the synthesis of wrong viral proteins and along the way viral components collect in the host cells but infective viruses do not arise.
  • It is effective only against DNA viruses and clinically utility is limited to Herpes simplex.

8. Trifluridine

  • Trifluridine is a fluorinated pyrimidine nucleoside analog.
  • It is structurally very similar to thymidine, the only difference being the replacement of a methyl group on the pyrimidine ring of thymidine with a trifluoromethyl group.
  • Once converted to the triphosphate, the agent is believed to competitively inhibit the incorporation of thymidine triphosphate into viral DNA and, to a lesser extent, to be incorporated into viral DNA, leading to the synthesis of a defective DNA that renders the virus unable to reproduce.
  • Trifluridine monophosphate is an irreversible inhibitor of viral thymidine synthase.
  • Trifluridine is active against HSV-1, HSV-2, and vaccinia virus.
  • It is generally considered to be the drug of choice for treatment of HSV keratoconjunctivitis and recurrent epithelial keratitis.

C. Treatment of Respiratory Virus Infections

a. Oseltamivir and Zanamivir

  • Orthomyxoviruses that cause influenza contain the enzyme neuraminidase, which is essential to the life cycle of the virus.
  • Oseltamivir and zanamivir are transition-state analogs of the sialic acid substrate and serve as inhibitors of the enzyme activity of viral neuraminidase.
  • These drugs prevent the release of new virions and their spread from cell to cell.
  • Oseltamivir and zanamivir are effective against both Type A and Type B influenza viruses and they do not interfere with the immune response to influenza A vaccine.

b. Amantadine and Rimantadine

  • The therapeutic spectrum of the adamantane derivatives, amantadine and rimantadine, is limited to influenza A infections, for which the drugs have been shown to be equally effective in both treatment and prevention.
  • Amantadine is chemically unique (a tricyclic amine) and unrelated to any nucleic acid precursor.
  • The primary antiviral mechanism of amantadine and rimantadine is to block the viral membrane matrix protein, M2, which functions as a channel for hydrogen ions.
  • This channel is required for the fusion of the viral membrane with the cell membrane that ultimately forms the endosome which is created when the virus is internalized by endocytosis.

c. Ribavirin

  • Ribavirin is a purine nucleoside analogue which has a broad spectrum antiviral activity, including that against influenza A and B, respiratory syncytial virus and many other DNA and double stranded  RNA viruses.
  • Its mono and triphosphate derivatives generated intracellularly inhibit GTP, viral RNA synthesis and mRNA capping.

D. Treatment of HIV Infection

  • Prior to approval of zidovudine in 1987, treatment of HIV infections focused on decreasing the occurrence of opportunistic infections that caused a high degree of morbidity and mortality in AIDS patients rather than on inhibiting HIV itself.
  • In present condition, a highly active regimen is employed that uses combinations of drugs to suppress replication of HIV and restore the number of CD4+ cells and immunocompetence to the host.
  • This multi drug regimen is commonly referred to as “highly active antiretroviral therapy,” or HAART.
  • There are five classes of antiretroviral drugs, each of which targets one of four viral processes.
  • These classes of drugs are nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, entry inhibitors, and the integrase inhibitors. The current recommendation for primary therapy is to administer two NRTIs with either a protease inhibitor, an NNRTI, or an integrase inhibitor.

a. Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)

  • NRTIs are analogs of native ribosides (nucleosides or nucleotides containing ribose), which all lack a 3’-hydroxyl group.
  • Once they enter cells, they are phosphorylated by a variety of cellular enzymes to the corresponding triphosphate analog, which is preferentially incorporated into the viral DNA by virus reverse transcriptase.
  • Because the 3’-hydroxyl group is not present, a 3’-5’-phosphodiester bond between an incoming nucleoside triphosphate and the growing DNA chain cannot be formed, and DNA chain elongation is terminated.
  • Azidothymidine(Zidovudine)
  • Approved in 1987, the first agent available for treatment of HIV infection is the pyrimidine analog, 3’-azido-3’-deoxythymidine (AZT).
  • AZT has the generic name of
  • Zidovudine is a thymidine analogue (azidothymidine, AZT), an important advance in the treatment of HIV infections.
  • Like other nucleoside analogues, it is phosphorylated to the5’ triphosphate after uptake into a cell.
  • After phosphorylation in the body, zidovudine triphosphate selectively inhibits viral reverse transcriptase (RNA dependent DNA polymerase).
  • AZT triphosphate binds more strongly to the viral reverse transcriptase than to the cell DNA polymerase, and the reverse transcriptase binds AZT triphosphate in preference to deoxythymidine triphosphate.
  • AZT inhibits HIV reverse transcription, but it can also interfere with cell DNA synthesis
  • Stavudine (d4T)
  • Stavudine is an analog of thymidine, in which a double bond joins the 2’ and 3’ carbons of the sugar.
  • Stavudine is a strong inhibitor of cellular enzymes such as the β and γ DNA polymerases, thus reducing mitochondrial DNA synthesis and resulting in toxicity.
  • Didanosine (ddI)
  • The second drug approved to treat HIV-1 infection was didanosine (dideoxyinosine, ddI), which is missing both the 2’- and 3’-hydroxyl groups.
  • Upon entry into the host cell, ddI is biotransformed into dideoxyadenosine triphosphate (ddATP) through a series of reactions that involve phosphorylation of the ddI, amination to dideoxyadenosine monophosphate, and further phosphorylation.
  • Like AZT, the resulting ddATP is incorporated into the DNA chain, causing termination of chain elongation.
  • Tenofovir (TDF)
  • Tenofovir is the first approved drug that is a nucleotide analog, namely, an acyclic nucleoside phosphonate analog of adenosine 5’-monophosphate.
  • It is converted by cellular enzymes to the diphosphate, which is the inhibitor of HIV reverse transcriptase.
  • Cross-resistance with other NRTIs may occur, but some AZT-resistant strains retain susceptibility to tenofovir.
  • Lamivudine (3TC)
  • Lamivudine (2’-deoxy-3’-thiacytidine, 3TC) is approved for treatment of HIV in combination with AZT, but it should not be used with other cytosine analogs due to antagonism.
  • Lamivudine terminates the synthesis of the proviral DNA chain, and it inhibits the reverse transcriptase of both HIV and HBV.
  • However, it does not affect mitochondrial DNA synthesis or bone marrow precursor cells.
  • Emtricitabine (FTC)
  • Emtricitabine, a fluoro-derivative of lamivudine, inhibits both HIV and HBV reverse transcriptase.

b. Nonnucleoside reverse transcriptase inhibitors(NNRTIs):

  • These non-nucleoside inhibitors target different sites in the reverse transcriptase to those targeted by the nucleoside analogues.
  • Delavirdine
  • Delavirdine is an inhibitor of CYP450–mediated drug metabolism, including that of protease inhibitors.
  • Efavirenz
  • Efavirenz treatment results in increases in CD4+ cell counts and a decrease in viral load comparable to that achieved by protease inhibitors when used in combination with NRTIs.
  • Efavirenz is extensively metabolized to inactive products.
  • Efavirenz is a potent inducer of CYP450 enzymes and, therefore, may reduce the concentrations of drugs that are substrates of the CYP450.
  • Etravirine
  • Etravirine is the first second-generation NNRTI.
  • It is active against many of the strains of HIV that are resistant to the first-generation NNRTIs.
  • Nevirapine
  • Nevirapine is an inducer of the CYP3A4 family of CYP450 drug-metabolizing enzymes.
  • Nevirapine increases the metabolism of protease inhibitors, but most combinations do not require dosage adjustment.

c. Protease inhibitors

  • The maturation of a retrovirus virion involves the cleavage by a virus protease of the Gag and Gag–Pol proteins to form the virion proteins.
  • If this processing does not take place the virion does not acquire infectivity.
  • Peptide mimics of the cleavage site in the protein have been developed and these compounds can fit into the active site of the HIV protease.
  • The result is that fewer virions bud from HIV infected cells and those virions that do bud are noninfectious. The examples of protease inhibitors are given as:
    • Amprenavir
    • Atazanavir
    • Darunavir
    • Fosamprenavir
    • Indinavir
    • Lopinavir
    • Nelnavir
    • Ritonavir
    • Saquinavir
    • Tipranavir

d. Entry inhibitors

  • After an HIV-1 virion has bound to a cell the transmembrane glycoprotein gp41 must fuse the envelope with the membrane of the cell if the virion contents are to be delivered into the cytoplasm.
  • For this, gp41 must undergo a conformational change initiated by interaction between different regions of the molecule.
  • A number of drugs have been developed that can inhibit fusion between the membranes of an HIV-1 virion and a potential host cell.
  • They do this by binding to gp41 and inhibiting the conformational change.
  • Enfuvirtide
  • Enfuvirtide was the first of a new class of antiretroviral drugs known as entry inhibitors.
  • Enfuvirtide is a fusion inhibitor.
  • Enfuvirtide is a 36-amino-acid peptide with the sequence of a gp41 region that binds to gp41, preventing the conformational change.
  • Maraviroc
  • Maraviroc is the second entry inhibitor.
  • HIV may express preference for either the CCR5 co-receptor or the CXCR4 co-receptor or both.
  • Maraviroc blocks the CCR5 co-receptor that works together with gp41 to facilitate HIV entry through the membrane into the cell.

e. Integrase inhibitor

  • Raltegravir is the first of a new class of antiretroviral drugs known as integrase inhibitors.
  • Raltegravir specifically inhibits the final step in integration of strand transfer of the viral DNA into own host cell DNA.

References

  1. Denyer S.P, Hodges N, Gorman S.P and Gilmore B.F. 2011. Hugo and Russell’s Pharmaceutical Microbiology. Eighth edition. A John Wiley & Sons, Ltd. Publication. Page no.194-198.
  2. Clark M.A, Finkel R, Rey J.A, and Whalen K. 2012. Lippincott’s Illustrated Reviews: Pharmacology. Fifth edition. Lippincott Williams & Wilkins, a Wolters Kluwer business. 351 West Camden Street Two Commerce Square Baltimore, MD 21201. Page no.461-480.
  3. Tripathi K.D. 1994. Essentials of Medical Pharmacology. Third edition. Jaypee Brothers Medical Publishers (P) Ltd. B-3 EMCA House 23/23B, Ansari Road, Daryaganj, New Delhi 110 002, India. Page no.717-722.

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