Antiviral Agents

Now we're onto discussing antivirals! I've spoken about them a little bit for PHAR2210, but I'll be talking about even more drugs in this post. Yay drugs.

Nucleoside/Nucleotide Analogues

Nucleoside/nucleotide analogues are fairly close to the structure of a real nucleoside/nucleotide, so they get incorporated into viral DNA but cause instability or chain termination. They generally need to be triphosphorylated by viral enzymes or by host enzymes in order to become active.

Nucleoside/nucleotide analogues are mostly active against herpes viruses such as herpes simplex virus (HSV), varicella zoster virus (VZV) and cytomegalovirus (CMV), though they are also active against HIV and hepatitis viruses. HSV is usually treated with acyclovir or penciclovir cream. Oral antivirals, such as valaciclovir and famciclovir, are more effective. Treatment can reduce the risk of serious sequelae, such as HSV-1 encephalitis. VZV is not usually treated in children, but in adults (who have a more severe form of chickenpox or may have shingles), acyclovir, famciclovir and/or valacyclovir may be given. Hepatitis B can be treated and even occasionally cured with nucleoside analogues, though the main aim is usually to suppress viral replication.

Acyclovir and Valacyclovir

Acyclovir is an analogue of guanosine. It is phosphorylated once by herpes virus thymidine kinase, and then twice more by host enzymes. A prodrug of acyclovir, valacyclovir, has a different side chain that improves its oral bioavailability (3-5x that of oral acyclovir).

Penciclovir and Famciclovir

Penciclovir is pretty similar to acyclovir, but it has a longer half-life. Famciclovir is a prodrug of penciclovir with higher oral bioavailability.

Ganciclovir and Valganciclovir

Ganciclovir is a guanosine analogue with IV, oral and intravitreal formulations. The intravitreal formulation, which is an implant, can be used to treat CMV retinitis (a complication of CMV that mainly occurs in HIV patients). Unfortunately, ganciclovir is very toxic and may suppress the bone marrow. Valganciclovir, the valyl ester of ganciclovir, has higher oral bioavailability and less toxicity.

Ribavirin

Ribavirin is an analogue of both guanine and adenine. It inhibits the RNA polymerase of RNA viruses, and has multiple targets in other viruses. Daily oral ribavirin, in conjunction with weekly interferon injections, are used to treat hepatitis C. Ribavirin is also effective against respiratory syncytial virus (RSV) and Lassa virus. Unfortunately, ribavirin can cause anaemia and thrombocytopaenia, and may have interactions with HIV drugs.

Matrix protein inhibitors

The only matrix protein inhibitor I'll talk about in this post is amantadine, which is only effective against influenza A (and even then has no effect against some strains, such as H1N1 or H3N2). It blocks the ion channel protein M2, which transports hydrogen ions and lowers the pH in the virus core, which in turn results in M1 protein dissociation from the ribonucleoprotein. Treatment with amantadine can shorten the illness and reduce viral shedding. Amantadine also has neurological effects and can be used in nerve pain and Parkinson's disease.

Neuraminidase inhibitors

Neuraminidase inhibitors, such as zanamivir and oseltamivir, block neuraminidase (!), which is a viral enzyme that cleaves receptors containing sialic acid, allowing viral particles to dissociate from the host cell. They are also used to treat influenza.

HIV drugs

See earlier post: Chemotherapy III: Antiviral Drugs