Antiviral resistance Flashcards
What is the difference between prophylaxis and therapy?
Prophylaxis is treatment/drugs given to a patient as a preventative measure before coming into contact with the aetiologic agent e.g. vaccines.
Therapy is the treatment provided after the host has been infected.
What is the difference between antivirals and poisons/antibiotics?
Antiviral need to be very specific since viruses are within host cells and using cell machinery.
What do antiviral drugs usually target?
Viral enzymes
What are substrate analogues and how do they work?
Molecules almost identical to the substrate with specific modifications on it. This allows them to bind to viral enzymes and inhibit the enzyme.
How do nucleoside analogues work?
Nucleoside analogues are very similar in shape to nucleosides which viruses must use to make more genetic material. This greatly slows down viral replication allowing the immune system to deal with the virus before it spreads to too many cells.
What is acyclovir and how does it work?
Treats herpes
It is a nucleoside analogue closely resembling guanosine but missing the 3 prime OH group. This missing 3 prime OH group makes acyclovir a chain terminator, since once the virus incorporates the acyclovir into its growing chain of DNA replication stops.
Acyclovir is a prodrug which is pharmacologically inactive until they are metabolized into an active form within the body. Acyclovir is administered in an unphosphorylated form and will not be incorporated into DNA until it becomes triphosphorylated. Inside human cells there are human enzymes that normally phosphorylate nucleosides into monophosporylate nucleotides however these enzymes do not work on acyclovir. However the viral encoded enzyme thymidine can put the first phosphate group onto the acyclovir. Thymidine kinase will only be present inside a cell that is already infected by herpes virus. Every other cell will not have the enzyme.
Once that first phosphate on then the cellular kinase enzymes can add the second and third phosphate on resulting in a triphosphate nucleotide precursor that can be incorparated into the host DNA.
The triphosphorylated acyclovir could be incorporated into both human and viral DNA as its copied however it has a higher affinity to viral DNA polymerase so is more likely to be incorporated into the viral DNA.
One method of resistance is a mutation of the thymidine kinase preventing the initial phosphorylation of the acyclovir. However this is rare because a mutation in thymidine kinase has a significant fitness cost and there isn’t enough of a selection pressure (unless you are taking acyclovir constantly) for the viral mutation to propgate well.
What is the wishlist for influenza virus?
- Targets essential gene or function
- Effective against all types
- Easy to administer for sick patients
- Few side effects for healthy patients
How do adamantanes work?
Targets M2 protein ion channels on influenza A blocking the influx of H+ ions through the channel. This prevents the acidification of the core of the virus which is necessary for the virus to leave the endosome. However a single point mutation e.g. serine to asparagine on position number 31 prevents the binding of the adamantanes drug with little fitness cost allowing the evolution of a resistant virus.
How do neuraminidase inhibitors work?
Neuraminidases are enzymes that cleave sialic acid groups from glycoproteins and are required for influenza virus replication.
Relenza and tamiflu bind to sialic acid preventing its cleavage therefore the virus cannot exit and spread to other cells.
How does baloxavir work?
Blocks viral polymerase activity. Again resistance is a single point mutation.
Give 4 examples of HIV antivirals
- Fusion inhibitors - inhibit viral entry by preventing fusion of viral envelope with plasma membrane
- Protease inhibitors - Inhibits protease enzymes that cut large viral precursor proteins into smaller units used in the mature virus.
- Reverse transcriptase inhibitors
- Intergrase inhibitor - inhibts intergration of viral DNA into host DNA
