Antiviral Drugs

 

Antiviral Drugs

 

 

           All antiviral drugs which have been developed till date are virostatic (tending to inhibit viral replication) in nature because viruses are dependent on the host cell for replication, therefore it is not possible to create true virucidal drugs.

 

Classification of antiviral drugs

-Depending upon the mode & site of action & chemical substances antiviral drugs are classified as:-

1.      Inhibitors of viral penetration & attachment

-Gamma globulins, Arbidol, Pleconaril, Maraviroc

2.      Inhibitors of viral translation, transcription & replication

a)      Inhibitors of nucleic acid synthesis

i)       Purine analogues: eg- Aciclovir, Ganciclovir, Vidarabine, Penciclovir, Famciclovir

ii)     Pyrimidine analogues: eg- Zidovudine, Idoxuridine, Trifluridine, Sorivudine, Cytarabine

iii)   Pyrophosphate analogues: eg- Foscarnet

b)      Protease inhibitors: eg- Saquinavir, ritonavir, Indinavir

3.      Inhibitors of viral assembly & release

a)      M₂ inhibitors: eg- Amantadine, Rimantadine

b)      Neuraminidase inhibitors: eg- Zanamivir, Oseltamivir

4.      Immunomodulators

a)      Interferons: eg- Interferon-alpha, Peginterferon alpha-2A

b)      Interferons inducers: eg- Polyinosinic-Polycytidylic acid(Poly I-Poly C)

5.      Miscellaneous agents

a)      Thiosemicarbazone: eg- Methisazone

b)      Antibiotics: eg- Rifampicin, Actinomycin D

c)      Others: eg- Suramin, Levamisole, Dextran sulphate

1)      Inhibitors of viral attachment and penetration

a)      Gamma globulin (IgG) – A protein fraction obtained from plasma of normal individuals.

·         It contains variety of antibodies against specific viral antigens.

·        

 

MOA:- Antibodies can neutralise some viruses and thus prevent their attachment to the cell membrane and thus prevent their penetration into the host cell.

·         IgG are ineffective orally has to be administered parenterally.

·         Used in human medicine to prevent progression of measles, rabies, poliomyelitis etc.

·         Protection against viral infections is short lived after single injection.

b)      Arbidol – it is an antiviral drug used for treatment of influenza virus infection in human beings.

 

MOA: - prevents viral entry into target cells by preventing contact between the virus and target cells. Fusion between viral capsid and cell membrane of target cell is inhibited. Also induces interferon production and activates the phagocytic function of macrophages. More effective in preventing infection from RNA viruses than DNA viruses.

c)      Pleconaril- against rhinoviruses and enteroviruses, picornaviridae family.

MOA- It acts by binding to a hydrophobic pocket in viral protein-I (VP1), the major protein which comprises capsid of picornaviruses.

Also prevents attachment of viruses to host cell. In enteroviruses it prevents the virus from exposing its RNA.

d)      Maraviroc- Novel antiviral drug used in treatment of HIV infection.

MOA:- It acts by inhibiting the chemokine receptor (CCR5) which is an essential co-receptor for most HIV strains and necessary for the entry process of virus into the host cell.

Drug binds to CCR5 receptor:- blocks the HIV protein gp120 , a glycoprotein exposed on surface of HIV envelope from associating with receptor HIV becomes unable to enter into human macrophage and T cells .

 

2)      Inhibitors of viral translocation, transcription and replication

A.    Inhibitors of viral nucleic acid synthesis

i)       Purine analogues

a)      Aciclovir: Synthetic guanosine nucleotide analogue

      Most prescribed antiviral drug because of its effectiveness against herpes virus.

·         Chemistry: A guanosine derivative in which a linear side chain has been substituted for the cyclic sugar of naturally occurring guanosine molecule, it lacks true sugar moiety.

·         Gertrude B. Elion was awarded a noble prize in medicine in 1988, partially for development of aciclovir.

  

 

      MOA : Aciclovir is a synthetic guanosine analogue so it substitute guanosine in DNA synthesis and inhibits viral replication.

·         Efficacy of Aciclovir depends upon its conversion into triphosphate form.

·         Aciclovir is safe to host because it inhibits the viral DNA polymerase 10 to 30 times more than the host cell polymerase and also because the host cells are very less capable of activating the drug ( Aciclovir to Aciclovir monophosphate )

 

Antiviral spectrum: Aciclovir has antiviral activity against a variety of DNA viruses, especially the herpes group of viruses. It has no effect on latent viruses, only effective against actively replicating viruses.

Viral resistance: 1)   Due to altered/deficient viral thymidine kinase enzyme.

2)      Lack of specific thymidine kinase enzyme naturally in viruses.

 

Pharmacokinetics:

·         Oral administration:  poorly absorbed from GIT.

·         I/V administration: peak conc. in plasma immediately.

·         After absorption, widely distributed throughout body fluids and tissues including CSF & CNS.

·         Eliminated unchanged in urine via glomerular filtration & tubular secretion.

 

Side effects:

-GIT disturbances: nausea, vomiting, diarrhoea.

-I/V administration of drugs causes transient renal insufficiency.

- Phlebitis may occur after I/V administration.

-topical application causes local irritation.

- Reversible leucopoenia and anaemia in cats.

Contraindications & Precautions:

-contraindicated in hypersensitive patients

-not used in renal impairment & during dehydrated states.

-rapid infusion avoided as may cause renal damage

 

Drug interactions:- not used with nephrotoxic drugs. Eg: aminoglycosides.

Clinical uses:-

-useful in treating herpes infections

-useful in treating conjunctivitis and keratitis caused by equine herpes virus.

b)      Ganciclovir:- similar to aciclovir

Ø  Differs from aciclovir structurally only by addition of a hydroxymethyl group on the aciclovir side chain.

Ø  Poorly absorbed after oral administration.

Ø  Excreted unchanged in urine.

Ø  Myelosuppression & CNS effects are adverse effects mainly.

Ø  Also effective against cytomegalo virus.

Ø  Not used more due to its toxicity.

c)      Penciclovir:- also inhibitory for hepatitis B virus in addition to above.

Ø  It doesn’t cause termination of DNA chain because it has 3’ hydroxy group (unlike aciclovir)

Ø  Poorly available after oral administration

Ø  Used either I/V or topically.

d)      Famciclovir:- converted in vivo via first pass metabolism to Penciclovir.

-used orally for reaction of herpes virus infections

e)      Vidarabine (adenosine arabinoside)

Ø  Analogue of adenosine

Ø  Active against herpesvirus, poxvirus, rhabdovirus, hepadnaviruses & some RNA tumour viruses.

Ø  It is phosphorylated to its triphosphate derivative in host cell which inhibits viral DNA polymerase.

Ø  It terminates the extension of newly synthesized strands of nucleic acid.

Ø  Vidarabine triphosphate also inhibits ribonucleotide reductase, RNA polyadenylation & transmethylation reaction.

Ø  It is metabolised to lesser active hypoxanthine arabinoside by adenosine deaminase that acts synergistically with parent compound.

Ø  Mutagenic & carcinogenic in animals.

ii)   Pyrimidine analogues

a)             Idoxuridine: analogue of thymidine. Effective against herpes viruses & poxviruses

MOA:- 

Ø  Also inhibits DNA polymerase enzyme

Ø  Idoxuridine is rapidly inactivated by nucleosidase in vivo.

Uses:-

Ø  In herpes simplex keratoconjuctivitis in humans.

Ø  In herpes keratitis in feline.

Ø  Idoxuridine produces irritation, lacrimation, leukemia, photophobia like side effect.

Ø  Used as 1% solution every hour.

b)   Trifluridine:

Ø  Fluorinated Pyrimidine nucleoside resembling thymidine in structure

Ø  Phosphorylated to its triphosphate form that competes with thymidine triphosphate for DNA polymerase for incorporation into viral DNA.

Ø  It is also incorporated in host DNA

Ø  Toxic systemically

Ø  Primarily used as anti-herpes antiviral drug

Ø  Less toxic than idoxuridine

Ø  Superior than idoxuridine in Rx of feline herpetic keratitis

Ø  Used as 1% solution- used in 6-12 hrs

c)      Sorivudine

Ø  Synthetic Pyrimidine analogue.

Ø  It has high potency & selectivity against Varicella-Zoster virus.

Ø  It uses viral kinase enzyme to be converted into mono & di phosphate Sorivudine & then to triphosphate Sorivudine which inhibits DNA synthesis. Triphosphate is not incorporated into DNA but acts as competitive inhibitor of viral polymerase. It is active against most species in herpes virus family.

d)      Cytarabine

Ø  Cytotoxic pyrimidine nucleotide.

Ø  Originally developed as antileukaemic drug.

Ø  MOA:- It inhibits nucleotide reductase & DNA polymerase & depresses the reduction of cytidylic acid to deoxycytidylic acid, thus depleting the pool of deoxycytidine triphosphate available for DNA synthesis.

Ø  Effective against herpes simplex & Varicella-Zoster virus infection.

e)      Zidovudine

Ø  Analogue of thymidine

Ø  Effective against reteroviruses only because of its action on viral reverse transcriptase enzyme.

Ø  MOA:- it is phosphorylated in host cell by cellular enzymes to zidovudine triphosphate which selectively inhibits viral reverse transcriptase (RNA dependent DNA polymerase). Incorporation of triphosphate form into the growing viral DNA strands results in chain termination & inhibition of DNA synthesis.

Ø  Mammalian alpha-DNA polymerase is resistant to zidovudine but gamma-DNA polymerase in host cell mitochondria is fairly sensitive to drug may be basis for unwanted effects.

Ø  First line drug in Rx of AIDS in human beings

iii)   Pyrophosphate analogues

a)      Foscarnet- Foscarnet Na is an inorganic pyrophosphate analogues, poorly soluble in water.

MOA:-

Ø  Structural mimic of the anion pyrophosphate and acts as a DNA polymerase inhibitor.

Ø  Doesn’t undergo significant intracellular metabolism, but blocks directly the pyrophosphate binding site of viral polymerase & inhibits cleavage of pyrophosphate from deoxynucleotide triphosphate

Ø  Direct & selective action on DNA polymerase/ reverse transcriptase.

B.     Protease inhibitors

Ø  These drugs prevent viral replication by inhibiting the activity of enzyme proteases, which are responsible for proteolytic cleavage b/w structural or enzymatic proteins those from part of the viruses.

Normally when viral RNA is translated into a polypeptide sequence, the nascent protein sequence is assembled in long chain that includes various structural or enzymatic proteins. Before they become active, they must cut by viral proteases.

Ø  Viral proteases are enzymes which converts nascent protein sequence into functional proteins.

Ø  These drugs are effective against certain types of RNA viruses & retroviruses.

a)      Saquinavir:

Ø  First viral protease inhibitor marketed for use in HIV therapy.

Ø  Reversibly & selectively binds to active site of HIV protease; prevents polypeptide processing & subsequent virus maturation

Ø  Virus particles are non-infectious

 

3)      Inhibitors of viral assembly & release

A.    M2 inhibitors

a)      Amantadine- drug used upto 1966, not prescribed nowadays.

MOA:

·         Amantadine also has antiparkinsonian effect

·         It is effective against influenza A virus not against influenza B virus.

b)      Rimantadine:

more   potent, longer lasting & better tolerated than Amantadine

B.     Neuraminidase inhibitors:

Ø  used to treat influenza infections

Ø  acts by inhibiting viral neuraminidase enzyme found on surface of influenza viruses

Ø  enzyme cleaves sialic acid groups from glycoproteins & enables the virus to be released from host cell

Ø  neuraminidase inhibitors by blocking the viral neuraminidase protein, prevent the virus from escaping the host cell & thus prevents the spread of infection to new cells

a)      Zanamivir

b)      Oseltamivir: Tamiflu – against avian influenza

 

4)      Immunomodulators

A.    Interferons: it is a family of potent cytokines which posses antiviral, immunomodulatory & antiproliferative actions. Produced by mammalian cells in response to various inducers including viruses & in turn causes intracellular changes leading to antiviral state in cells of same species.

MOA:-

Main effect:-(1.) inhibition of viral protein synthesis via induction of interferon specific proteins

Interferons + tyrosine kinase

                                                      

(2.)Phosphorylation of cellular proteins

Induction of transcription of interferon induced proteins like  2’-5’-adenylate synthetase & protein kinase

                                                      

                      

(3)Inhibition of viral protein synthesis

 

Ø  Interferons also induce a phosphodiestrase that cleaves a portion of t-RNA & prevents peptide elongation

Ø  Also causes activation of Mx proteins, thus interferes with m-RNA synthesis & stimulation of methylase enzyme, inhibits the mrna cap methylation

Ø  Activation of glycosyltransferase blocks---- protein glycosylation & processing----- inhibiting virus maturation

Ø  Interferons are species specific but disease non-specific

Ø  Effective against almost all viruses except adenoviruses which are resistant to interferons.