Antivirals Flashcards
What makes making antivirals much harder than making antibiotics?
It is difficult to distinguish between virus replicative mechanisms and host replicative processes, mainly because viruses use our own replicative processes to replicate, unlike the bacterial processes which we can target.
What is the therapeutic index?
We use the therapeutic index to find an acceptable balance between damage done to the patient (the host) and the virus.
What are the three main ways in which antivirals work?
Targetting viral enzymes
Nucleoside analogs that inhibit nucleic acid replication.
Target specific viral factors (Directly Acting Antivirals)
What does acyclovir mimic?
It works by mimicking the structure of guanosine, making it a nucleoside analog, but it doesn’t have the bottom half of the molecule (specifically the 3’ hydroxyl group).
How does acyclovir work?
Mimics guanosine.
Acts as a chain terminator and prevent further transcription of viral DNA.
Why doesn’t acyclovir cause the same damage to people?
Acyclovir is only activated inside virus-infected cells.
Its specificity is largely due to phosphorylation of acyclovir to acyclovir monophosphate by virus-encoded thymidine kinase.
Subsequent phosphorylation to acyclovir triphosphate by cellular acyclovir monophosphate has a higher affinity for viral DNA polymerase than for host cell polymerase.
Although resistance to acyclovir is rare, how can it occur?
Mechanisms of resistance include deficient viral thymidine kinase; and mutations to viral thymidine kinase or DNA polymerase, altering substrate sensitivity.
What are the structures of adamantanes and what do they work against?
Adamantanes are cyclic amines with bulky, cage-like structures.
It is active against influenza A only.
How does an influenza virus expel its DNA into a host cell?
Once inside an endosome, tetrameric ion channels in the viral membrane allow the flow of protons into the virus.
This disrupts the interactions between the matrix proteins and nuclear proteins and causes the virus to fall apart, releasing its DNA.
How do adamantanes work?
It works by sitting in the middle of the tetrameric ion channel blocking the entry of protons into the cell and so preventing it from splitting apart.
What is one key problem with adamantanes?
It only takes single point mutations, e.g. S31N, to cause resistance.
This resistance also has little cost to the virus’s fitness, virulence or transmission (so no longer using adamantanes is unlikely to cause any change in this gene’s prevalence).
What is rational drug design?
Creating drugs based on our knowledge of viral structures and processes.
What is neuraminidase?
Neuraminidase is an enzyme that cleaves sialic acid.
What would be the result of a virus not having neuraminidase?
Without neuraminidase, the virus covered in haemagglutinins would stick onto the receptors on the old cell (containing sialic acid)
What do neuraminidase inhibitors prevent?
The spread of a virus through a host.
