Antivirals I

(Catherine)

What kind of virus is the herpes virus?

DNA virus

What kinds of treatments are used for herpes?

- Drugs inhibiting viral DNA replication
- Drugs inhibiting fusion/entry of the virus into the host cell

What kind of virus is HIV?

Retrovirus

What kinds of treatments are used to treat HIV?

- Drugs inhibiting fusion/entry of virus into the host cell
- Drugs inhibiting reverse transcription
- Drugs inhibiting integration of provirus into host cell genome
- Drugs inhibiting viral maturation

What kind of virus is the Hep C virus?

RNA virus

What kind of treatments are used for Hep C?

- Drugs inhibiting viral RNA replication
- Drugs inhibiting viral maturation

What kind of virus is the influenza virus?

RNA virus

What kind of treatments are used for influenza?

- drugs inhibiting uncoating of the virus
- drugs inhibiting release of progeny virions

What kind of virus is the corona virus?

RNA virus

What kind of treatments are used for corona virus?

- Drugs inhibiting viral RNA replication
- Drugs inhibiting viral maturation
- Antibody treatments

Do herpes viruses contain double or single strand DNA?

Double strand

How does the herpes virus acquire a functioning polymerase?

The virus carries its own code for the polymerase in its virions but relies on the host cell to express the polymerase

Are herpes viruses enveloped?

Yes

What are common viruses in the herpes virus family?

- Herpes simplex virus (HSV)
- Varicella-zoster virus (VZV)
- Cytomegalovirus (CMV)
- Eppstein-Barr virus

What drugs are commonly used to treat herpes viruses?

- Acyclovir
- Valacyclovir
- Penciclovir
- Famciclovir
- Trifluridine
- Docosanol

Acyclovir is an acyclic (nucleoside/nucleotide) analog

Nucleoside

What does a natural nucleoside require in order for DNA replication to work?

A 3'OH group

What is the main issue with using Acyclovir?

Low oral bioavailability

Best route of admin for Acyclovir (due to its BA)

Apply topically or use as a prodrug

What is the prodrug version of acyclovir?

Valacyclovir

What is the oral bioavailability of Valacyclovir?

70%

Why does Valacylovir have a better BA than Acyclovir?

Valacylovir can be taken up by peptide transporters and once absorbed, it can be converted into acyclovir by hydrolysis in the liver

What does acyclovir need to be converted to in order to be active?

Acyclovir-Triphosphate (TP)

Describe the MOA of acyclovir/valacyclovir?

- Acyclovir enters herpes virus-infected cell
- Viral thymidine kinase phosphorylates Acyclovir into Acyclovir-MP (traps molecule)
- Acyclovir-MP--> DP --> TP (active)
- Acyclovir-TP competes with natural nucleoside-TP for incorporation into DNA during replication
- Acyclovir-ATP interferes with DNA replication and limits # of new virions that can be made

What are the two outcomes of Acyclovir-TP competing with dGTP for DNA replication?

- Acyclovir-TP binds to viral DNA pol and stops dGTP from becoming incorporated
- Acyclovir-TP gets incorporated directly into DNA and leads to strand termination (due to lack of 3'OH)

What makes acyclovir very specific for virus-infected cells compared to healthy cells?

- Viral thymidine kinase converts Acyclovir into its MP version much more efficiently than a normal thymidine kinase of a host cell
- Viral DNA pol is inhibited more by Acyclovir-TP than DNA polymerase of the host cell

What can lead to resistance to acyclovir/valacyclovir?

- Mutations in viral thymidine kinase
- mutations in in viral DNA pol

Describe the molecular structure of docosanol

An aliphatic long-chain (C22) alcohol

Why is docosanol considered a detergent?

Contains a hydrophilic and hydrophobic end

MOA of docosanol

Interferes with fusion of host cell plasma membrane with viral envelope --> prevents viral entry

CMV infections mostly occur in what kinds of patients?

Patients with advanced immunosuppression

Why do CMV infections appear in patients with advanced immunosuppression?

Due to reactivation of a latent infection/virus that the patient already carries

What nucleoside analog drugs are used to treat CMV?

Ganciclovir/Valganciclovir

What can lead to resistance to Ganciclovir/Valganciclovir?

Mutations in the kinase that phosphorylates ganciclovir once it enters the host cell

What drugs don't rely on phosphorylation in the host cell (thus avoiding resistance)?

- Cidofovir (nucleotide analog)
- Foscarnet (pyrophosphate analog)

Why doesn't Cidofovir require phosphorylation when it enters the host cell?

Already has a phophoryl group attached

Drugs with "fo" in their name are what kind of analog?

Nucleotide analogs

If a patient develops resistance to cidofovir or foscarnet, what kind of mutation do they likely have?

A mutation in the viral DNA polymerase (instead of a kinase)

Why is cidofovir less specific than ganciclovir?

Less specific because it doesn't require activation by viral kinase and can thus be incorporated into DNA of healthy cells

Why does cidofovir need to be administered IV?

It is a charged molecule with poor BA

Side effect of cidofovir and foscarnet

Nephrotoxicity (must be excreted by active tubular secretion)

What is pyrophosphate?

- A byproduct of nucleotide incorporation into DNA during replication
- It binds to a specific pyrophosphate binding site before it gets released from DNA polymerase

MOA of Foscarnet

Mimics pyrophosphate and blocks its binding site to inhibit DNA synthesis (won't get released from DNA pol)

Why is foscarnet also only administered IV?

Due to poor BA and nephrotoxicity

How can foscarnet cause seizures?

Foscarnet can form complexes with Ca2+ and Mg2+ ions and cause imbalances in serum electrolytes

What kind of virus is the Hep A virus?

RNA virus

What kind of virus is the Hep B virus?

DNA virus