Abu Ayesha

In common with bacterial infection, some viral infections may be confined to particular tissues or organs while other viral infections may become generalized, affecting many tissues and systems. When feasible, immunization is the preferred method for controlling viral infections in humans and animals. However, the absence of vaccines for many major viral diseases and new virulent virus subtypes in animals has confirmed the necessity for effective antiviral chemotherapy.

 Unlike

bacteria or fungi, viruses cannot replicate independently and, because of this restriction, they are obligate intracellular parasites. Host cell provide the requirements for viral replication including energy, protein synthesis and RNA or DNA replication. Virus replication occurs in sequential steps : Attachment Penetration Release of viral genome Expression of viral genome

 Effective

antiviral drugs inhibit virus specific events related to virus replication rather than host cell synthetic activities, such as nucleic acid or protein synthesis. antiviral drugs are nucleic acid analogues which interfere with DNA or RNA synthesis. mechanism of action include interference with virus-cell binding, interruption of virus uncoating and inhibition of virus progeny release from infected host cell.

Many

Other

Ribavarin, active against RNA and DNA viruses

Vidarabine, active against herpes Virus

1972

Oseltamivir, antiinfluenza activity

1977 1992

1998

Aminothiozole derivatives which interact with the helicase primase complex of herpesviruses discovered; broad-spectrum antiviral activity of a phosphorothioate oligonucleotide reported

2002

Amantadine, anti-influenza activity

Lamivudine, anti-HIV activity

1966
2013

Tibotec, against New hepatitis C

Viral interference discovered; later the name interferons was given to the molecules which exerted antiviral activity

1957
1950 Idoxuridine, active against herpes virus
1959

Rimantadine, anti-influenza activity

Zidovudine, first antivirul drug approved for treatment of HIV infections 1985

DRACO; a team of researchers at MITs Lincoln Lab. Has designed a drug that can identify cells that have been infected by any virus, then kill those cells to terminate the infection.

1993

2014

Saquinavir, first protease inhibitor of HIV

1995

 All

viruses which cause disease in humans and animals replicate in host cells and, accordingly, they follow a similar sequence during their replicative cycle. viral infections have relatively short incubation periods, whereas slowly progressing viral infections have long incubation periods. viral infections are characterized by periodic reactivation of virus replication, often related to stressful environment conditions or immunosuppression associated conditions or other factors.

Acute

Latent

Antiviral therapy is aimed at preventing virus entry into host cells, interfering with uncoating, genome replication or assembly and release of virus from host cells. Stages of viral replication and possible points at which antiviral drugs or components of the immune system can interrupt replicative events are presented in below given table :Categories of drugs or immune components with antiviral activity Peptide analogues of attachment proteins; fusion protein inhibitors; neutralizing antibodies Ion channel blockers Inhibition of viral DNA polymerase, RNA polymerase, reverse transcriptase Nucleoside analogues Interferons, antisense oligonucleotides Stage of replication where antiviral drugs or immune components act

Attachment to host cell

Uncoating Transcription of viral genome Replication of viral genome Translation of viral proteins

Protease inhibitors
Interferons Neuraminidase inhibitors; specific antibodies plus complement; destruction of infected cells by cytotoxic T cells of NK cells

Post-translational changes in proteins

Assembly of virion components Release of virions by budding or cell lysis

The major classes of antiviral drugs, grouped according to their modes of action, are reviewed briefly in below give table :Antiviral drug Mode of action Antiviral spectrum Comments Acyclovir Cidofovir Inhibits viral DNA polymerase Inhibits viral DNA synthesis Herpesviruses, particularly herpes simplex virus Herpesviruses, poxviruses, papillomavirus, adenovirus Amantadine
Ion channel blocker which interferes with virus uncoating Influenze A virus; other viruses which encode proteins that form ion channels may be susceptible Influenze A virus; may be effective against some viruses which utilize ion channels

Not effective against latent viral infections Long tissue half-life allows infrequent dosing
Antiviral activity of amantadine in animals is limited Antiviral activity of rimantidine in animals is limited Because of its toxic effects if given systematically, it is used for topical Rx only Can be used prophylatically and therapautically
Retains activity against viruses which have become resistant to other classes of antiretroviral drugs

Rimantidine

Ion channel blocker which interferes with virus uncoating

Incorporated into DNA with interference in nucleic acid synthesis and viral gene expression

Idoxuridine

Herpesviruses and poxviruses

Oseltamivir

Interacts with neuraminidase, inhibiting its activity

Influenza A and Influenza B Human immunodeficiency type 1 virus

Human immunodeficiency type 1 virus

Enfuvirtide

Prevents fusion of HIV-1 with host cell membrane

Disrupts the catalytic activity of HIV-1 reverse transcriptase
Inhibits reverse transcriptase activity of retroviruses & also inhibits the DNA polymerase of hepatitis B virus

Delaviridine

Cross-resistance to other drugs in this class usually applies

Lamivudine

Retroviruses & Hepatitis B virus

When combined with zidovudine, a marked synergistic antiviral effect results

anti-influenza drugs amantadine and rimantidine inhibit virus replication at an early stage in the replicative cycle of influenza A viruses. The mechanism of action of these antiviral drugs relates to virus uncoating shortly after endocytosis of virus by the host cell.

The

The antiviral drug amantadine, which has long been known as a specific inhibitor of influenza A virus, is a tricyclic amine. Amantadine inhibits an early step in the replication of influenza A virus and its antiviral activity is confined to influenza virus. Following attachment to host cell sialic acid moities on cell surface glycoproteins by means of influenza envelope glycoproteins or haemagglutinins, the virus is endocytosed. At this early stage of its replication cycle, the virus is contained in a membrane bound compartment, the endosome. As part of its normal function, the endosome becomes acidified. The low pH causes a conformational change in the virion haemagglutinin protein, and fusion of the virion envelope and the endosomal membrane occurs, releasing the nucleocapsid into the cytoplasm of the host cell. However, in the presence of amantadine, the matrix protein, M1, does not dissociate from the ribonucleoprotein which remains in the cytoplasm instead of entering the nucleus. The M2 proteins in nucleocapsid seems to form a polymeric tube-like structure through which hydrogen ions from the acidified endosome enter the virion and dissociate M1 from the ribonucleoprotein. By interfering with the ion channel function of M2 protein, amantadine inhibits acid-mediated dissociation of the ribonucleoprotein complex early in replication, a process essential for uncoating of the single-stranded RNA genome.

Inhibitors of influenza neuraminidase activity interfere with release of influenza A virus and influenza B virus from host cells. When influenza viruses complete their replicative cycle, they bud from the cell membrane. Release of newly formed virions from infected cells requires neuraminidase for cleavage of sialic acid residues from the cell membrane envelope present on the budding virions. If this does not take place, the budding of haemagglutinin protruding from the virion surface with persisting sialic acid residues on newly released adjacent virions causes aggregation of the virions on the cell surface. The neuraminidase inhibitors oseltamivir and zanamivir are sialic acid analogues which specifically inhibit influenza A & B virus neuraminidase activity.

Attachment of Virus haemagglutin to sialic acid which act as a cell receptor on host cell membrane

Endocytosis

Ion Channel Blockers amantadine Rimantadine

Conformational changes in the virion haemagglutin protein in endosomal vesicle, mediated by the low pH, promotes fusion of viral envelope with endosomal membrane

Release of nucleocapsid into host cell cyotoplam followed by uncoating

Transfer of viral RNA into host cell nucleus

Nucleoside analogue; Ribavarin

Viral mRNA

Replication of viral RNA

RNA poymerase

Viral enzymes

Regulatory proteins

Protein Synthesis on host cell ribosomes

Assembly of Virions
Neuraminidase inhibitors ; Zanamivir

Structural proteins

Release of virions by budding following cleavage of sialic acid residues on the host cell surface by newly formed virions

Replicative cycle of a influenza virus, a RNA virus, and points at which antiviral drugs interfere with replication or release of newly formed viruses from host cell

Studies have demonstrated that neuraminidase activity at the time of virion release is essential for disease production. Oseltamivir is a transition-state analogue of sialic acid which is a potent selective inhibitor of influenza A & B neuraminidase activity. The interaction of oseltamivir with neuraminidase causes a conformational change in the enzymes active site which inhibits its activity. As a consequence of neuraminidase inhibition, aggregation and clumping of virions occur at the infected cell surface, reducing the spread of virus within the respiratory tract.

Many antiviral drugs inhibit viral genome replication. Most of these drugs are nucleoside analogues which inhibit viral polymerases, especially DNA polymerases. Before these compounds can exert their antiviral effect, they must undergo intracellular phosphorylation to the active triphosphate form. Phosphorylated nucleoside analogue inhibit polymerase by competing with natural substrates and they are usually incorporated into growing DNA chain where they often terminate elongation. Acyclovir and related drugs in this category, which include famciclovir, penciclovir & ganciclovir are all nucleoside analogues. These antiviral drugs, which are especially effective against herpesviruses, inhibit viral DNA polymerase or inhibit viral DNA synthesis by slowing and eventually terminating chain elongation.

The nucleoside analogue acyclovir is structurally similar to the natural nucleoside deoxyguanosine. Acyclovir has selective activity against a number of herpesviruses including herpes simplex & varicella-zoster viruses. This drug inhibits DNA polymerase in a number of herpesviruses. Before this antiviral drug can exert its effect, however, it must be phophorylated. Herpes simplex virus encodes a thymidine kinase which activates the drug by phosphorylation to acyclovir monophosphate, and host cell enzymes complete the conversion to the diphosphate form and finally to the triphosphate form. The acyclovir triphosphate also becomes incorporated into the viral DNA where it acts as a chain terminator.

Attachment of virus to host membrane

Penetration

Uncoating, release of viral genome and transfer of viral DNA into host cell nucleus

Transcription of viral DNA into viral mRNA Protein synthesis on host cell ribosomes
Viral enzymes

Replication of viral DNA

DNA polymerase
DNA polymerase Inhbitors Acyclovir Cidofovir Famciclovir Penciclovir Ganciclovir

Structural Proteins
Assembly of virions Release of virions by budding

Replicative cycle of a herpesvirus, a DNA virus, and points at which antiviral drugs interfere with replication .

drugs which interfere with virus attachment and entry into host cells prevent subsequent stages of virus infection. Such drugs also provide an opportunity for components of immune system to clear viruses from the body fluids and host tissues.

Antiviral

The synthetic peptide enfuvirtide prevents the fusion of HIV-1 with the host cell outer membrane, thereby preventing infection of CD4+ T cells. The sequence of the synthetic peptide is derived from a portion of the transmembrane gp41 region of HIV-1 which mediates fusion of the virus membrane lipid bilayer with that of the host cell. Enfuvirtide inhibits infection of CD4+ T cells by free virus particles and also prevents cell-to-cell transmission of HIV-1 in vitro. Human immunodeficiency type 1 strains develop resistance to enfuvirtide through specific mutations in the enfuvirtide-binding domain of gp41.

Attachment of virus to CD4 receptor present mainly on T lymphocytes

Fusion inhibitor
Enfuvirtide
Nucleoside reverse transcriptase inhibitors Lamivudine Stavudine Zidovudine Non-nucleoside reverse transcriptase inhibtors Delavirdine Efavirenz Nevirapine

Fusion of viral envelope with chemokine receptors on host cell plasma membrane, uncoating of virus and release of viral genome into cytoplasm
Viral reverse transcriptase mediates reverse transcription of single stranded RNA, forming RNA-DNA hybrid

RNA template is partially degraded by ribonuclease H followed by synthesis of second DNA strand, forming viral double-stranded DNA, referred to as provirus Viral double-stranded DNA, the provirus is transported to the cell nucleus & integrated into the host chromosomal DNA by viral integrase enzyme Although provirus may remain quiescent for some time, it replicates as the cell divides. Activation of the infected cell by an extrinsic stimulus results in transcription of proviral DNA into genomic single-stranded RNA and later, several mRNA molecules

Viral mRNA molecules Two identical strands of genomic single-stranded viral RNA

Regulatory proteins Structural proteins

Synthesis of viral precursor proteins on host cell ribosomes

Assembly of virions

Release of assembled virions by budding; precursor proteins are cleaved by viral proteases as virions mature

Protease inhibitors Amprenavir Ritonavir Saquinavir

Replicative cycle of a retrovirus, a RNA virus, and points at which antiviral drugs interfere with replication or maturation.

These antiviral drugs selectively inhibit HIV-1 by binding to a site on the reverse transcriptase that differs from that bound by natural nucleoside analogues. These compounds induce conformational change in reverse transcriptase which disrupts its catalytic activity. Delaviridine & nevirapine, two examples of these antiviral drugs, are non-competitive inhibitors of HIV-1 reverse transcriptase. These drugs do not acquire intracellular phosphorylation to acquire antiviral activity.

The non-nucleoside reverse transcriptase inhibitor delaviridine is a bis-heterparylpiperazine compound which selectively inhibits HIV-1. Delaviridine induces a conformational change in the reverse transcriptase which disrupts its catalytic activity. Because the target site of this antiviral drug is HIV-1 specific & is non-essential for the enzyme, resistance can develop quickly.

A number of nucleoside analogues, including lamivudine, stavudine & zidovudine, are inhibitors of HIV reverse transcriptase. These nucleoside reverse transcriptase inhibitors are activated intracellularly by phosphorylation with cellular kinase and their triphosphate forms competitively inhibit reverse transcriptase. The triphosphate form of these antiviral agents terminates elongation of the proviral DNA chain.

cytosine analogue lamivudine is a reverse transcriptase inhibitor of HIV-1 & HIV-2 and an inhibitor of the DNA polymerase of hepatitis B virus. Cellular enzymes convert lamivudine to the triphpsphate form which competitively inhibits hepatitis B DNA polymerase.

The