Lecture 5: Ribavirin Flashcards
Describe the structure of ribavirin
Guanosine analogue
Given as a prodrug
Difference is that it has an incomplete purine ring - when this is phosphorylated, it is trapped inside the cell
What property of ribavirin makes it useful for a range of viruses?
Very broad acting antiviral agents - against both RNA and DNA viruses
What 2 viruses is ribavirin FDA approved for?
Hep C
Human respiratory syncytical virus
Explain the differences in Hep C and Respiratory syncytical viruses
Genetic make up: Hep C is a negative sense RNA virus and Respiratory syncytical virus is a positive sense RNA virus Genetic life cycle: Hep C is a chronic virus whereas respiratory syncytical virus has a short life span Cell trophism (type of cells that they target): Liver for Hep C and Resp tract for human respiratory syncytical virus
What was the old management for Hep C?
Ribavirin + interferon (a cytokine that causes an innate immune response by cells)
How effective is the combination of Ribavirin + interferon for treatment of Hep C?
Combining the 2 drugs increases efficacy greatly compared to monotherapy
Half of patients respond to treatment and half do not
How is the human respiratory syncytial virus described as?
Negative stranded
Paramyxovirus
How does human respiratory syncytial virus present?
General cold like symptoms
However can be fatal for young, elderly and immunocompromised
What is a treatment option for human respiratory syncytial virus and how effective is it?
Ribavirin
Mild benefits at best
Describe briefly the 3 proposed mechanisms that ribavirin works by?
1) Inhibition of inosine monophosphate dehydrogenase (IMPDH)
2) Error catastrope by nucleotide mis-incorportation by the RdRp
3) Inhibition of RNA polymerase via the RdRp
Describe the mechanism of action of ribavirin via inhibition of IMPDH by ribavirin 5’ monophosphate
IMPDH converts inosine MP to xanthisine MP
IMPDH enzyme is needed to maintain GTP levels
GPT = cellular RNA/DNA synthesis
Ribavirin MP is a competitive inhibitor of IMPDH therefor e less GTP and therefore less RNA/DNA produced
[see slide for image]
What is the evidence to support the mechanism of action via inhibition of IMPDH by ribavirin 5’ monophosphate?
~40% Reduction in GTP pool seen up to the the concentration of 20μM - this has a minor effect on virus growth rate
Major drop in virus growth rate seen has higher concentrations but GTP is unaffected, suggesting a second mechanism
Describe the mechanism of action of ribavirin via error catastrophe in RNA virus replication?
Viral polymerase (RdRp) works hard to ensure replication of the virus genome
However this process is error prone ~1 in every 1000
Rate is close to the limit of viability i.e. if the rate was higher than the virus will die due to non functional proteins = error catastrophe
[see slides for images]
What is the evidence to support the mechanism of action via error catastrophe in RNA virus replication?
Virus replication rate is reduced - increased with higher concentration of ribavirin
Specifically: reduction in infectious virus but same amount of viral genome therefore not inhibiting replication at this point but just infectious ability = error catastrophe
Comparing the genome sequence between no ribavirin and ribavirin shows an increase in mutations
Ribavirin incorporates in the place of a G or A nucleotide - it can then base pair with either U or C but it is not specific to either = 50% chance of error
Note that this mechanism of action has been proven to not be true for Hep C
[see slides for images]
Describe the mechanism of action of ribavirin via inhibition of RNA polymerase by the RdRp
Binds to viral polymerases and shows down the copying rate = reduction in genome synthesis
Ribavirin fits into the polymerase active site
[see slide]
