Anti-viral Drugs

Anti-influenza drugs

Influenza is a negative sense RNA virus which has a lipid envelope with three key cell surface proteins: hemagglutinin (HA), neuraminidase (NA), and an M2 ion channel.

To enter the host, the envelope binds to the cell using HA, which binds sialic acid.

The M2 protein allows H+ inside, allowing entry of the virus particle into the cell.

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

Anti-influenza drugs have specifically targeted these cell surface glycoproteins.

Amantadine, rimantandine

These block the M2 ion channel to stop the entry of virus particles.

They are no longer recommended in influenza due to high rates of resistance.

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

Oseltamivir, zanamivir

These are neuraminidase inhibitors which prevent the virus leaving the cell.

They are used in the treatment and prophylaxis of influenza A and B, although evidence as to their effectiveness remains weak. 

Ribavirin

This drug inhibits viral RNA synthesis. It is also used in RSV infections in immunocompromised children, although the evidence behind this is weak.

It is used against hepatitis C and viral haemorrhagic fever. 

Anti-herpes drugs

Herpesviruses are a group of double stranded DNA viruses with 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 cannot be elongated.

Acyclovir

This is converted to acyclovir triphosphate, which inhibits viral DNA polymerase, inhibiting viral DNA replication.

Ganciclovir

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

It then inhibits the viral DNA polymerase stopping DNA replication.

It is used to treat human cytomegalovirus and herpesvirus.

It also exists as a prodrug, which is called Valganciclovir, which is typically used to treat CMV in patients with AIDS or after an organ transplant.

Cidofovir

This is a cytosine analogue which inhibits the DNA polymerase of cytomegalovirus.

Foscarnet

This inhibits viral DNA polymerisation by inhibiting the pyrophosphate binding site on viral DNA polymerase.

It is used to treat acyclovir resistant herpes infection.

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 the 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.

In the host, reverse transcriptase converts viral RNA to DNA.

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

The virus translates proteins as one long polyprotein and then uses a HIV protease to cleave this into mature proteins.

HIV Fusion Inhibitors

Enfuvirtide

Enfuvirtide binds to the gp41 subunit of HIV-1 to stop it from interacting with gp160, preventing entry into the host cell.

Maraviroc

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

Non-Nucleoside Reverse Transcriptase Inhibitors – Nevirapine, efavirenz

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

Integrase inhibitors – Raltegravir (suffix = -gravir)

These inhibit the integrase enzyme to prevent the virus from integrating its newly made DNA into the host DNA. 

HIV protease inhibitors – Saquinavir, ritonavir 

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

Protease inhibitors are recommended to be used alongside nucleoside analogues.

They can cause metabolic changes, e.g., diabetes, hyperlipidaemia and weight gain. 

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