Classification of Antiviral Drugs

Classification of Antiviral Drugs

The antiviral compounds vary greatly in complexity and include nucleoside analogs, synthetic oligonucleotides, oligo-saccharides, and also natural products of plants and some inor-ganic and organic compounds. The antiviral agents available against viruses can be classified as: (a ) nucleoside analogs, (b ) non-nucleoside polymerase inhibitors, (c ) protease inhibi-tors, (d ) neuraminidase inhibitors, (e ) M2 channel blockers, and (f ) interferons.

Nucleoside Analogs

Numerous analogs of naturally occurring nucleosides have been synthesized in the laboratory for their possible use against viruses. These nucleoside analogs that act by inhibiting the enzyme viral polymerase are generally activated by phos-phorylation by cellular or viral kinases.

    The commonly used nucleoside analogs are acyclovir, vala-cyclovir, penciclovir, and famciclovir, ganciclovir, azidothymi-dine (AZT), ribavirin, and dideoxynucleosides (dideoxyinosine, dideoxycytidine, stavudine, and lamivudine).

◗ Acyclovir

Acyclovir (ACV) is a synthetic guanine nucleoside analog. It differs from the nucleoside guanosine by having an acyclic (hydroxyethoxymethyl) chain instead of a ribose or deoxyribose sugar. The ACV has selective action against herpes viruses, such as herpes simplex virus (HSV) and varicella zoster virus. It acts through the viral enzyme thymidine kinase, encoded by these herpes viruses.

·           The ACV is used for treatment of HSV infections, such as HSV encephalitis, disseminated herpes, and other serious life-threatening manifestations of herpes infections. The compound inhibits HSV replication in infected host cells but is ineffective to resolve the latent HSV infection.

·           The ACV at higher doses is also effective against varicella zoster virus (VZV) infections. The compound is less effec-tive against this virus because ACV is phosphorylated less efficiently by the VZV thymidine kinase.

◗ Valacyclovir

Valacyclovir is the valyl ester derivative of ACV that is well absorbed. Its bioavailability is 2–5 times more than ACV and  is usually recommended for the treatment and suppression of genital herpes infection.

◗ Penciclovir

Penciclovir is a guanosine analog. It has a higher affinity for HSV thymidine kinase than ACV but has a lower affinity for HSV DNA polymerase than ACV. It acts by inhibiting viral DNA polymerase and also as a chain terminator. It is used for the treatment of genital herpes infection.

·           Penciclovir is effective for treatment of both HSV and VZV. After administration, the drug is available in more quantity and persists for a longer time in infected cells than ACV.

·           The penciclovir also has some antiviral activity against cytomegalovirus and Epstein–Barr virus.

◗ Ganciclovir

Ganciclovir is a guanine nucleoside, chemically related to ACV. It differs from ACV in having a single hydroxymethyl group in the acyclic side chain. It acts as a chain terminator in subse-quent termination of viral DNA replication. It is highly effec-tive against all herpes viruses including cytomegalovirus. It is more active against cytomegalovirus (CMV) than ACV. It is more useful in treating severe CMV infections in immunocom-promised hosts, such as acquired immunodeficiency syndrome (AIDS). Ganciclovir resistance is a noted problem of therapy with ganciclovir.

◗ Azidothymidine

Azidothymidine (AZT) is the synthetic analog of thymidine and was the first useful antiviral agent to be reported for treat-ment of HIV infection. It acts by blocking the synthesis of pro-viral DNA by inhibiting viral reverse transcriptase. The latter is 100 times more susceptible to inhibition by AZT than host cellular DNA polymerase.

·           Azidothymidine is widely used for treatment of HIV infec-tion. It is currently used for the management of HIV with reduced CD4 T-cell counts (400–500 or less) to prevent pro-gression of the disease.

·           It is also used for treatment of pregnant HIV-infected women.

·           It has been shown to reduce or prevent the trans-mission of HIV from the mother to the baby.

The drug, however, is toxic and costly. Emergence of resistance to AZT is also a worrisome problem.

◗ Ribavirin

Ribavirin is a synthetic analog of the nucleoside guanosine. Ribavirin triphosphate is the active form of the drug. It dif-fers from guanosine by having a base ring, which is incomplete and is open. Ribavirin is effective against many DNA and RNA viruses. It acts mainly by preventing replication of the viruses by inhibiting nucleoside biosynthesis, mRNA capping, and other processes essential for viral replication.

·           When administered as an aerosol, ribavirin has been shown to be effective for treatment of severe respiratory syncytial viral infection in children and for treatment of severe influ-enza and measles in adults.

·           Intravenous ribavirin is also effective for treatment of infections caused by influenza B virus and Rift Valley virus, and Lassa, Crimean-Congo, and other hemorrhagic fevers.

·           Ribavirin in combination with interferon-alpha (IFN-a) is shown to be effective against the infection caused by hepa-titis C virus.

◗ Dideoxynucleosides

Dideoxynucleosides (e.g., dideoxyinosine, dideoxycytidine, stavudine, and lamivudine), the analogs of nucleosides, have been synthesized for use against HIV. These agents act by inhibiting HIV replication by blocking the enzyme reverse transcriptase. These compounds inhibit the enzyme reverse transcriptase by preventing DNA chain elongation. These com-pounds are usually recommended for the treatment of AIDS in patients not responding to therapy with AZT. These are also used in combination with AZT for treatment of the AIDS cases.

◗ Other Nucleoside Analogs

These consist of a number of compounds including idoxuridine, trifluorothymidine, fluorouracils, and adenine arabinoside.

These are analogs of thymidine. They inhibit synthesis and rep-lication of viruses:

·           by inhibiting the synthesis of thymidine, a nucleic acid essential for synthesis of viral DNA or

·           by replacing thymidine with itself in the viral DNA.

These are effective against viruses such as herpes simplex virus (HSV), replication of which is associated with synthesis of large volume of viral DNA.

Idoxuridine

Idoxuridine was the first antiviral drug to be used for treat-ment of HSV but now has been replaced by trifluorothymidine and fluorouracil. These two compounds are more effective and less toxic for treatment of HSV. Fluorouracil is also used for topical treatment of warts caused by human papilloma viruses.

Adenine arabinoside

Adenine arabinoside is a purine nucleoside analog similar to adenosine. It differs from adenosine in having arabinose instead of ribose as the sugar moiety. It was used as an impor-tant antiviral agent for treatment of herpes virus infection until ACV become available. Recently, many other nucleoside analogs have been evaluated as antiviral agents for treatment of infections caused by HIV, hepatitis B virus, and herpes viruses.

Non-Nucleoside Polymerase Inhibitors

Non-nucleoside polymerase inhibitors include foscarnet and related phosphonoacetic acid. These inhibitors inhibit replica-tion of viruses by binding to the pyrophosphate binding site of the DNA polymerase to block binding of nucleotides. Foscarnet specifically inhibits DNA polymerase of all herpes viruses and reverse transcriptase of the HIV. The compound has also shown antiviral activity against hepatitis B virus.

Nevirapine, delavirdine, and efavirenz are the other non-nucleoside polymerase inhibitors with different mechanisms of action. They bind to sites on the enzyme different from the substrate. These compounds are usually given in combination with other nucleoside analogs to delay or prevent emergence of drug resistance in HIV.

Protease Inhibitors

Saquinavir, indinavir, ritonavir, nelfinavir, and amprenavir are some of the examples of protease inhibitors. These agents act specifically on the unique structure of HIV protease, which is essential for the production of a functional HIV. Human immunodeficiency virus strains showing resistance to these drugs occur through mutation of the HIV protease. Hence, a combination of protease inhibitor with AZT and a nucleoside analog is usually recommended to reduce replication of viruses to minimum undetectable levels.

Other Antiviral Drugs

Amantadine (Adamantanamine hydrochloride, symmetrel) and rimantadine are anti-influenza drugs useful for treatment of influenza virus infections. These are not effective for treat-ment of influenza B or C viruses. These act specifically against influenza A virus by their ability to bind and to block protein channel by the matrix protein (M2) of the influenza A virus. Resistance to these drugs occurs due to mutations, resulting in changed M2 matrix protein or hemagglutinin protein.

Amantadine and rimantadine are useful in reducing sever-ity of influenza A infection if taken within 48 hours of expo-sure. They are also useful as prophylactic agents in treatment of influenza A infection. Amantadine is also used for treatment of Parkinson’s disease. The drug, however, is toxic to the central nervous system.

Zanamivir (Relenza) and oseltamivir (Tamiflu) are the anti-viral compounds with clinical efficacy against both the influ-enza A and B viruses. They are potent inhibitors of the influenza neuraminidase. Without production of the enzyme neuramini-dase, the hemagglutinin of the virus binds to sialic acid on other viral particles, forming clumps and thereby preventing release of virus particles. In several clinical trials, both the agents have demonstrated efficacy with minimal side effects. If taken within 48 hours of infection, these drugs reduce the duration of illness.

Interferon

There are three classes of interferon: (i) interferon alpha (IFN-a), (ii) interferon beta (IFN-b), and (iii) interferon gamma (IFN-g). IFN-a occurs as at least 15 subtypes, the genes for which show 85% homology. Interferons are produced by leu-kocytes and many other cells in response to infection by virus, double-stranded RNA (dsRNA), endotoxin, and mutagenic and antigenic stimuli. The dsRNA is a potent stimulator. The viruses that replicate slowly and viruses that do not inhibit syn-thesis of host proteins are usually good inducers of the inter-ferons. IFN-g differs from other interferons in being released as lymphokines from activated T cells, natural killer cells, and occasionally from macrophages. Interferons exert antiviral effect by several pathways as follows:

a)        They cause increased expression of class I and class II MHC (major histocompatibility complex) glycoproteins, thereby facilitating the recognition of viral antigens by immune system.

b)       They activate the cells, such as natural killer cells and macrophages, the cells with the ability to destroy virus-infected targets.

c)        They directly inhibit replication of viruses.

Interferons are now being increasingly used for treatment of chronic hepatitis B and C virus carriers who are at risk to progress to cirrhosis and hepatocellular carcinoma. The interferon when given with ribavirin has proved to be more effective than interferon alone for treatment of hepatitis C virus infection. Currently, synthetic IFN-a is actively used against hepatitis A, B, and C viruses; papilloma virus; HSV; and rhinovirus. It is also used for the treatment of condylomata acuminatum.