Antiviral Drugs

• The drugs which are used in treatment of viral infections are called as “Antiviral Drugs”.

What are Viruses?

• Viruses are intra cellular parasites which can not replicate on their own and hence require host cells to replicate.
• They can infect all life forms.
• They have simple structure which contains,

1. An envelope: A lipid coating, in some cases it may be absent.
2. Capsid coat: Its a viral protein coat that covers the viral nucleic material.
3. Nucleic Material: It may be DNA or RNA.
4. Shapes may be different from simple to complex.

• Most viruses have particle size so small that they can not be watched from optical microscopes.

Classification:

• Viruses are classified by two main ways,

1. Using ICTV (International Committee on Taxonomy of Viruses).
2. Baltimore Classification.

1) ICTV Classification:

• ICTV classification is based on taxonomy of viruses and identifies nearly 80 families and 5000 subspecies of viruses.
• e.g. Chicken Pox virus: Varicella zoster (VZV)
• Order: Herpesvirales.
• Family: Herpesviridae.
• Sub family: Alphaherpesvirinae.
• Genus: Varicellovirus

2) Baltimore Classification:

• This scheme of classification is introduced by Nobel laureate “David Baltimore”.
• This scheme of classification classifies viruses on basis of,

1. Nucleic Acid: DNA or RNA.
2. Mode of Replication: positive sense or negative sense (Need of viral protein activation in host cells)
3. No. of Nucleic acid strands present: Single or Double.

• e.g. Chicken Pox virus: Varicella zoster (VZV)
• Group-I: as,

1. It has double stranded nucleic acid.
2. Nucleic acid present is DNA.
3. This virus does not uses a “Reverse Transcriptase” enzyme.

Replication Cycle of Viruses:

• Virus being an intracellular parasite, it can not replicate on its own and needs host cells for that purpose.
• The replication cycle of viruses involve following SIX steps.

1) Attachment:

• Using its envelope or capsid coats it forms an attachment with the host cell membrane or cell wall.
• This attachment is specific i.e. binding to specific protein or receptor on cell membrane, which decides host range of the virus.
• e.g HIV specifically binds with T4 Leucocytes and not others.

2) Penetration:

• After attaching to cell membrane they enter the cell through endocytosis process.
• In case of bacterias where cell walls are very strong viruses inject their genetic material while capsid remains outside the cell.

3) Uncoating:

• After entering the host cell the coating around the viral nucleic acid dissolves either by host / viral enzymes or simply dissociates.
• This stage releases the viral nucleic acid in the cell.

4) Replication:

• This step involves with replication of viral genome.
• Uncoated nucleic acid and certain viral enzymes initiate formation of viral mRNA which give rise to viral nucleic acid replication and formation of viral structural proteins inside the host cell.

5) Assembly:

• The formed material under fourth step is assembled in order to form new viruses.
• During assembling the modification of some viral proteins may takes place.

6) Release:

• Most viruses release from the cell by causing lysis or breakdown of the host cells.
• Some viruses e.g. HIV are released by budding in envelope form where they get their envelope which is mostly part of host plasma.

Antiviral Drugs Development:

• As  viruses are intracellular parasites which uses most delicate host cell machinery for replication, they are difficult to treat with normal drugs as it may cause harm to the host cells also.
• Vaccination is an effective way to build up immunity to the disease while developing the highly selective antiviral drugs to use the infected patients are the priorities.
• The prime areas of targeting are,

1. Preventing cell membrane binding of the viruses.
2. Prevention of new viruses from the cells.
3. viral mRNA.
4. Viral enzymes like Reverse Transcriptase, DNA/RNA polymerase.
5. Viral specific proteins that are not synthesized in the host cells.

Classification of Antiviral Drugs:

A) DNA Polymerase Inhibitors:

a) Purine Analogues:

• Acyclovir.
• Ganiciclovir.
• Valacyclovir.

b) Pyrimidine Analogues:

• Idoxuridine.

c) Non Nucleoside:

• Foscarnet.

B) Prevention of Penetration/Uncoating:

• Amantidine.
• Rimantidine.

C) mRNA Synthesis Inhibitors:

• Rabvirin
• Fomvirsen.

D) Neuraminidase Inhibitors:

• Oseltamivir (Tamiflu)
• Zanamivir.

E) Immunomodulators:

• Immunoglobulines.
• Interferons.
• Imiquimod.
• Palivizumab.

Acyclovir

• Its a purine analogue that inhibits viral DNA polymerase.
• Its a prodrug that gets activated to its active form after phosphorylation by “Thymidine kinase” inside the cell.
• Its 200X times greater affinity towards viral enzyme makes it a safer antiviral drug.
• It is a structural analogue of Guanosine.

Mechanism of Action:

• Acyclovir is a synthetic analog of the purine nucleoside, guanosine, with potent antiviral activity against herpes simplex viruses type 1 and 2, varicella-zoster virus and other viruses of the herpesvirus family.
• After conversion in vivo to the active metabolite acyclovir triphosphate by viral thymidine kinase, acyclovir competitively inhibits viral DNA polymerase by incorporating into the growing viral DNA chain and terminating further polymerization.

Side Effects / Adverse Effects:

1. Nausea, Diarrhea and vomiting.
2. Encephalopathy following IV administration.
3. Sore throat.
4. Hair loss.
5. Nephrotoxicity.
6. Thrombocytopenia.
7. Dry and flaky skin.

Therapeutic / Medicinal uses:

1. Treatment and prevention of genital herpes simplex virus.
2. Treatment of neonatal herpes simplex virus.
3. Herpes infection of eye.
4. Prevention of Herpes infection in immunocompromised patients.

Idoxuridine

• Its a pyrimidine analogue that inhibits the viral DNA polymerase.

Mechanism of Action:

• Idoxuridine has structural configuration similar to thymidine and hence gets accumulated in DNA but the Iodine atom in the structure of the Idoxuridine prevents base pairing and hence affects the growth of viral DNA.
• Because of cardiotoxicity the drug is used only by topical route.

Side effects / Adverse effects:

1. Corneal clouding.
2. Photophobia.
3. Damage to corneal epithelium.

Therapeutic / Medicinal Uses:

1. Herpes simplex keratitis.
2. Initial attacks of Herpes simplex.

Amantidine.

• Amantidine is a drug approved by USFDA for use as antiviral and as a antiparkinsonian.
• Both the effects have different and independent mechanism of actions.
• 

Mechanism of Action:

• Amantidine  inhibits a viral protein known as “M2” which is a proton channel and is involved in dissolution of the viral capsid coat to release viral nucleic acid in the host cell thereby preventing unpacking level during virus’s life cycle.

Side effects / Adverse effects:

1. Skin rashes.
2. Severe allergic reactions.
3. CNS side effects.

Oseltamivir.

• Oseltamivir is a neuraminidase inhibitor.
• Neuraminidase is an enzyme responsible for  cleaving of sialic acid which is responsible for breaking of cell membrane to release new virion particles.
• 

Mechanism of Action:

• Oseltamivir is an antiviral prodrug which after hepatic activation inhibits viral “Neuraminidase enzyme” and hence prevents release of new virions from infected cells.

Pharmacokinetics:

• Absorption: Good oral absorption with bioavailability of 75%.
• Distribution: VD is 23 to 26 L.
• Metabolism: Extensively by liver, does not affects Cytochrome P450.
• Excretion: Extensively from urine, biological half life is 1-3 hours after oral administration.