Antiviral Drugs

ANTIVIRAL DRUGS

PREPARED BY :- BURHAN NABI

Abu Ayesha

INTRODUCTION

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 genomeExpression 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.

Many antiviral drugs are nucleic acid analogues which interfere with DNA or RNA synthesis.

Other mechanism of action include interference with virus-cell binding, interruption of virus uncoating and inhibition of virus progeny release from infected host cell.

DEVELOPMENT OF ANTIVIRAL DRUGS

1950

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

1957

Idoxuridine, active against herpes virus

1959

Amantadine, anti-

influenza activity 196

6

Ribavarin, active

against RNA and DNA viruses

1972

Vidarabine, active

against herpes Virus

1977

Zidovudine, first antivirul drug approved for

treatment of HIV infections

1985

Lamivudine, anti-HIV activity

1992

Rimantadine, anti-

influenza activity 199

3

Saquinavir, first protease

inhibitor of HIV1995

Oseltamivir, anti-

influenza activity

1998

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

2002

DRACO; a team of researchers at MIT’s

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.

Tibotec, against

New hepatitis C

2013

2014

VIRAL INFECTIONS AND STRATEGIES FOR INTERRUPTING VIRUS REPLICATION All viruses which cause disease in humans and

animals replicate in host cells and, accordingly, they follow a similar sequence during their replicative cycle.

Acute viral infections have relatively short incubation periods, whereas slowly progressing viral infections have long incubation periods.

Latent viral infections are characterized by periodic reactivation of virus replication, often related to stressful environment conditions or immunosuppression associated conditions or other factors.

CONT….. 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

Stage of replication where antiviral drugs or immune components act

Peptide analogues of attachment proteins; fusion protein inhibitors; neutralizing antibodies

Attachment to host cell

Ion channel blockers Uncoating Inhibition of viral DNA polymerase, RNA polymerase, reverse transcriptase Transcription of viral genome

Nucleoside analogues Replication of viral genome

Interferons, antisense oligonucleotides Translation of viral proteins

Protease inhibitors Post-translational changes in proteins

Interferons Assembly of virion components

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

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 :-

CONT….

Antiviral drug

Mode of action Antiviral spectrum Comments

Acyclovir Inhibits viral DNA polymerase

Herpesviruses, particularly herpes

simplex virus

Not effective against latent viral

infections

Cidofovir Inhibits viral DNA synthesis

Herpesviruses, poxviruses,

papillomavirus, adenovirus

Long tissue half-life allows infrequent

dosing

Amantadine Ion channel blocker which interferes with virus

uncoating

Influenze A virus; other viruses which encode proteins that form ion

channels may be susceptible

Antiviral activity of amantadine in

animals is limited

Rimantidine

Ion channel blocker which interferes with virus

uncoating

Influenze A virus; may be effective against some

viruses which utilize ion channels

Antiviral activity of rimantidine in

animals is limited

Idoxuridine Incorporated into DNA with interference in nucleic acid

synthesis and viral gene expression

Herpesviruses and poxviruses

Because of its toxic effects if given

systematically, it is used for topical Rx

only

Oseltamivir Interacts with

neuraminidase, inhibiting its activity

Influenza A and Influenza B

Can be used prophylatically and

therapautically

EnfuvirtidePrevents fusion of HIV-1

with host cell membrane

Human immunodeficiency type

1 virus

Retains activity against viruses which have

become resistant to other classes of antiretroviral

drugs

Delaviridine Disrupts the catalytic activity of HIV-1 reverse

transcriptase

Human immunodeficiency type 1 virus

Cross-resistance to other drugs in this

class usually applies

Lamivudine Inhibits reverse transcriptase activity of

retroviruses & also inhibits the DNA polymerase of

hepatitis B virus

Retroviruses & Hepatitis B virus

When combined with zidovudine, a marked synergistic antiviral

effect results

ION CHANNEL BLOCKING COMPOUNDS

The 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.

Amantadine 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.

NEURAMINADASE INHIBITOR 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

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

endosomal membrane

Ion Channel Blockers

amantadineRimantadine

Release of nucleocapsid into host cell cyotoplam followed by

uncoating

Transfer of viral RNA into host cell nucleus

Replication of viral RNA

Viral mRNA

Nucleoside analogue; Ribavarin

Protein Synthesis on host cell ribosomes

Regulatory proteins

Viral enzymes

RNA poymeras

e

Assembly of Virions

Structural

proteins

Release of virions by budding following cleavage of sialic acid residues on the

host cell surface by newly formed virions

Neuraminidase inhibitors ; Zanamivir

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

Oseltamivir

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 enzyme’s 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.

ANTIVIRAL DRUGS WHICH INHIBIT VIRAL GENOME REPLICATION

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.

Acyclovir 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

Replication of viral

DNA

Protein synthesis on

host cell ribosomes

Viral enzymes

DNA polymeras

e

Structural Proteins

DNA polymerase Inhbitors

AcyclovirCidofovir Famciclovir Penciclovir Ganciclovir

Assembly of virions

Release of virions by buddingReplicative cycle of a herpesvirus, a DNA virus, and points at which antiviral drugs interfere with

replication .

ANTIRETROVIRAL DRUGS

Antiviral 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.

ENFUVIRTIDE

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 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 enzymeAlthough 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

Two identical strands of genomic single-stranded viral RNA

Viral mRNA molecules

Synthesis of viral precursor proteins on host cell ribosomes

Regulatory

proteinsStructura

l proteins

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

Assembly of virions

Protease inhibitors

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

maturation.

Fusion inhibitor

EnfuvirtideNucleoside

reverse transcriptase

inhibitorsLamivudine

StavudineZidovudine

Non-nucleoside reverse

transcriptase inhibtors

Delavirdine Efavirenz Nevirapine

Non-nucleoside reverse transcriptase inhibitors

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.

DELAVIRIDINE

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.

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

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.

LAMIVUDINE

The 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.

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