Lecture 5: Ribavirin Flashcards
Describe the structure of ribavirin
Guanosine analog.
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 syncytial virus
Explain the differences in Hep C and Respiratory syncytial viruses
Genetic makeup: Hep C is a negative sense RNA virus and Respiratory syncytial virus is a positive sense RNA virus
Genetic life cycle: Hep C is a chronic virus whereas respiratory syncytial virus has a short life span.
Cell tropism (a type of cells that they target): Liver for Hep C and Resp tract for the human respiratory syncytial virus.
What was the old management for Hep C?
Ribavirin + interferon for 24-48 weeks
How effective is the combination of Ribavirin + interferon for the 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 the 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 catastrophe by nucleotide misincorporation 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 xanthosine
MP IMPDH enzyme is needed to maintain GTP levels
GTP = cellular RNA/DNA synthesis
Ribavirin MP is a competitive inhibitor of IMPDH, therefore, less GTP and therefore less RNA/DNA produced
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 concentration of 20μM - this has a minor effect on virus growth rate.
Major drop in virus growth rate seen at 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 the 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 nonfunctional proteins = error catastrophe.
What is the evidence to support the mechanism of action via error catastrophe in RNA virus replication?
Virus replication rate is reduced - with a higher concentration of ribavirin.
Specifically: reduction in infectious virus but the same amount of viral genome therefore not inhibiting replication but inhibiting 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.
Describe the mechanism of action of ribavirin via inhibition of RNA polymerase by the RdRp
Binds to viral polymerases and slows down the copying rate = reduction in genome synthesis.
Ribavirin fits into the polymerase active site.
