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 Inhibitors – Zidovudine/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 Inhibitors – Nevirapine
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 inhibitors – Raltegravir (suffix = -gravir)
These inhibit the integrase to stop the virus integrating its newly made DNA into the host DNA
- HIV protease inhibitors – Saquinavir + 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