L4 - Ribavirin

Question 1

Why do we need antiviral drugs?

Answer 1

first line of defence against EMERGING PANDEMICS

Question 2

What are the 4 questions to ask when targeting the virus life cycle?

Answer 2

entry receptors?
How do genomes remain undetected?
Where do they replicate in cells?
How do they escape from cells?

Question 3

What is Ribavirin?

Answer 3

Guanosine analogue

Question 4

How is Ribavirin different to guanosine?

Answer 4

incomplete purine ring

modified in vivo by kinases to generate ribavirin-triphosphate

Question 5

How is Ribavirin administered?

Answer 5

aerosol

tablet delivery

Question 6

When was Ribavirin discovered?

Answer 6

early 1970s

Question 7

What viruses does Ribavirin work against?

Answer 7

RNA and (few) DNA

Question 8

What viruses are Ribavirin FDA approved for?

Answer 8

HCV

RSV

Question 9

What viruses are treated by Ribavirin but NOT FDA approved?

Answer 9

Lassa fever virus

CCHFV

Question 10

When has Ribavirin been used as a last resort?

Answer 10

Rabies

Milwaukee protocol - KETAMINE INDUCED COMA
RIBAVIRIN

Question 11

How many documented cases of rabies survival with no vaccine?

Answer 11

3

Question 12

How are HCV and HRSV different?

Answer 12

Genetic make-up

General life cycle

Cell tropism

Question 13

How is HCV ultimately fatal?

Answer 13

liver failure

Question 14

How is HCV treated by ribavirin?

Answer 14

Oral ribavirin + pegylated IFNa (combination)

Question 15

Can HRSV be fatal?

Answer 15

YES - young, elderly, immune compromised

Question 16

How is HRSV treated by RIbavirin?

Answer 16

aerosol - 12-18hrs

Question 17

What are the 3 mechanisms identified for how Ribavirin works?

Answer 17

1. Inhibition of IMPDH
2. Error catastrophe
3. Inhibition of RNA polymerisation via RdRp

Question 18

How does Ribavirin work by mechanism 1 (inhibition of IMPDH)?

Answer 18

competitive inhibitor of IMPDH

inhibits production of XMP and other compounds leading to GTP

all viruses need GTP for replication

Question 19

What does IMPDH do?

Answer 19

converts IMP to XMP (needed for production of GTP)

Question 20

What ribavirin concentration best reduces the GTP pool?

Answer 20

low conc. 20um

Question 21

What ribavirin conc best reduces viral growth?

Answer 21

high conc. 20-100um

Question 22

What does the contradicting effects of ribavirin on GTP and viral growth suggest?

Answer 22

secondary mechanism is involved

Question 23

How does mechanism 2 (error catastrophe) of ribavirin work?

Answer 23

ribavirin increases mutations

at 1000um, 15 mutations per genome = virus cannot survive

ribavirin pairs with C and U in place of A and G

Question 24

How does Ribavirin increase the error rate?

Answer 24

ribavirin incorporation in place of G/A nucleotides

Ribavirin can base pair with C or U

Question 25

What is the usual RdRp error rate?

Answer 25

1 x 10^-4

Question 26

What is mechanism 3 of ribavirin - inhibition of RNA polymerisation by the RdRp?

Answer 26

binds directly polymerases

5x reduced genome synthesis

fits in poymerase active site - mimics rNTP - occupies slightly diff. position

Question 27

What are drawback of ribavirin treatment>

Answer 27

monotherpay not good

cytotoxicity

stored in RBCs for 6 months

women need to avoid pregnancy

Question 28

Why is ribavirin still used despite side effects>

Answer 28

many viruses still without any treatments

used to treat infections with an otherwise fatal outcome

serious side effects are tolerated

Question 29

What is the future for ribavirin treatment?

Answer 29

VIRAMIDINE

Question 30

How is viramidine better than ribavirin?

Answer 30

lower toxicity
better liver targeting
better tissue specificity

Question 31

Does ribavirin treat SARS-CoV-2?

Answer 31

limited activity shown in human trials - can be used to treat