Antiviral drugs

a) Anti-influenza drugs

Influenza is a –ve sense RNA virus which has a lipid envelope with three key cell surface proteins:

–  Hemagglutinin (HA), Neuraminidase (NA), and a M2 ion channel.

– On entry, the envelope binds to the cell using HA which binds sialic acid

– M2 protein allows H+ inside acidifying vesicle, allowing endocytosis of the virus particle into the cell

– After replication is complete, neuraminidase cleaves sialic acid from surface allowing virus to leave cell

 

Therefore, anti-influenza drugs have specifically targeted these cell surface glycoproteins:

  • Amantadine + Rimantadine – These block the M2 ion channel to stop entry of virus particles

– They are used to treat influenza A early in infection

– Amantadine is also used to treat Parkinson’s as it blocks dopamine reuptake enhancing transmission

 

  • Ribavirin – This drug alters synthesis of GTP and inhibits the viral RNA polymerase to stop replication

– Used against influenza A and B, respiratory syncytial virus, hepatitis C

Side effects: Haemolytic anaemia, cough and is avoided in pregnancy as it is teratogenic

 

  • Oseltamivir + Zanamivir – These are neuraminidase inhibitors which prevent the virus leaving cell

– They are used in the treatment and prophylaxis of influenza A and B.

b) Anti-herpes drugs

This is a group of double stranded DNA viruses which have a lipid envelope.

– They characteristically infect a cell but then establish a latent infection. Stimulation of the cell may then allow replication causing a secondary infection after a delay.

 

Drugs targeting herpesviruses typically target the viral DNA polymerase needed to replicate dsDNA.

– They are base analogs that lack a terminal 3-OH which means the strand can’t be elongated

 

  • Acyclovir – Purine analogue. It is phosphorylated by viral thymidine kinase and then terminates strand.

 

  • Ganciclovir – This is a purine analogue that is phosphorylated to the triphosphate form.

– It then inhibits the viral DNA polymerase to stop DNA replication

– Used to treat human cytomegalovirus and Herpesvirus

Side effects: Neutropenia and thrombocytopenia

 

  • Cidofovir – This is a cytosine analogue which inhibits the DNA polymerase of cytomegalovirus

Side effects: Nephrotoxic –> so given with Probenecid

 

  • Foscarnet – This inhibits cleavage of pyrophosphate during viral DNA polymerization

– Therefore, inhibits viral DNA and RNA polymerase

– Used to treat acyclovir resistant herpes infection

 

c) Anti-HIV drugs

These drugs take advantage of the fact that HIV is a retrovirus which must integrate into the host cell DNA:

– To enter the cell, the gp41 subunit of HIV binds to gp160 glycoprotein which is necessary for interaction with CD4 that lets HIV enter the cell

– This also requires a CCR5 chemokine to allow the conformational change to occur

– Once inside, the reverse transcriptase converts HIV RNA –> DNA to integrate into the genome

– The virus then uses an integrase enzyme to insert itself into the host DNA

– HIV translates proteins as one long polyprotein and uses a HIV protease to cut this into mature proteins

 

  • HIV Fusion Inhibitors

Enfuvirtide – binds gp41 subunit of HIV-1 to stop it from interacting with gp160 preventing entry

Maraviroc – binds to host cells displaying CCR5 receptors preventing HIV entry into the cell.

 

  • Nucleoside Reverse Transcriptase InhibitorsZidovudine/Azidothymidine (AZT)

These are thymidine analogues which get incorporated into the DNA strand but lack a 3-OH group

– Therefore, they act as chain terminators, preventing DNA synthesis

– Given with hydroxyurea –> this stops ribonucleotide reductase stopping host pyrimidine synthesis to boost activity of these drugs

Side effects: Peripheral Neuropathy (+ specific effects for each drug)

 

  • Non-Nucleoside Reverse Transcriptase InhibitorsNevirapine

These bind away from the active site of the reverse transcriptase and cause a conformational change of shape in the enzyme inhibiting its function

Side effects: Induction of the CYP450 enzyme + Skin rash (Stevens-Johnson Syndrome)

 

  • Integrase inhibitorsRaltegravir (suffix = -gravir)

These inhibit the integrase to stop the virus integrating its newly made DNA into the host DNA

 

  • HIV protease inhibitorsSaquinavir + Ritonavir (suffix = -avir)

These inhibit the HIV-1 protease to stop polyprotein cleavage and virus maturation

– Protease inhibitors are recommended to be used in parallel with nucleoside analogues

– They have been shown to delay the progression of AIDs and recent evidence implies that disease may even be reversed to some degreed by adequate combination therapy.

 

Side effects: Metabolic changes –> Diabetes + Hyperlipidaemia + weight gain

– Cytochrome P450 inhibition

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