12- Mechanisms for Antivirals

Question 1

need for antiviral drugs?

Answer 1

no/ poorly effective vaccines for some human viruses

not everyone can be administered a vaccine

immune response to vaccine administration can take time, and multiple doses

Question 2

current use of antivirals?

Answer 2

treating acute/ chronic infections - e.g. influenza, HIV,

pre/post exposure prophylaxis - e.g. HIV with PrEP

prophylaxis for reactivated infection - e.g. CMV

Question 3

how is selective toxicity ensured with antivirals?

Answer 3

aims to inhibit virus replication without harming the infected cell by targeting differences in structure & metabolic pathways between the host and pathogen

targets viral proteins, not cellular proteins

Question 4

different modes of action of selected antivirals

Answer 4

preventing virus adsorption onto host cell

preventing penetration

preventing viral nucleic acid replication (e.g. with nucleoside analogues)

preventing maturation of virus

preventing virus release

Question 5

why is it so difficult to develop effective, non-toxic antivirals?

Answer 5

virus are obligate intrac. proteins - must replicate inside host cells, take over host cell machinery & use cellular proteins

high mutation rate - can give rise to quasi-species in one individual

antivirals must have selective toxicity for infected cells

some viruses can become latent - e.g. herpes, VZV hiding in dorsal ganglions

some viruses can integrate their genetic material into host cells

Question 6

acyclovir - viral targets?

Answer 6

HSV treatment for genital infections, encephalitis & recurrent genital herpes

VZV treatment for chickenpox & shingles

CMV & EBV prophylaxis
(herpes viruses)

Question 7

ganciclovir - viral targets?

Answer 7

CMV (i.v./ oral)

Question 8

Foscarnet - viral targets?

Answer 8

CMV (i.v./ local application)

Question 9

cidofovir - viral targets?

Answer 9

CMV (i.v.)

Question 10

acyclovir - mechanism of action against herpes virus?

Answer 10

selective toxicity for herpes virus infected cells

administered orally/ i.v./ topically - inactive acyclovir is modified by viral thymidine kinase = increase in phosphate residues convert acyclovir into active form, and makes it look more like a nucleotide/DNA base

viral DNA polymerase incorporates active acyclovir into viral DNA - causes DNA synthesis chain termination

no viral DNA synthesis = no viral proteins = no virus

Question 11

acyclovir - how is it selectively toxic?

Answer 11

HSV thymidine kinase has a higher affinity than cellular phosphokinase for acyclovir

active acyclovir has a higher affinity for viral DNA polymerase than cellular DNA polymerase

highly polar compound - will enter infected cells easily, harder for it to leave

selectivity ensures it only targets herpes virus infected cells, and has low background toxicity

Question 12

ganciclovir - mechanism of action?

Answer 12

targets CMV infected cells which doesn’t encode thymidine kinase BUT does encode UL97 kinase which has a similar function

inactive ganciclovir is administered via i/v or orally - enters infected cells

UL97 kinase increases number of phosphate residues = looks like a DNA nucleotide base

inhibits CMV DNA polymerase = DNA chain termination = no viral DNA synthesis or protein production

Question 13

Foscarnet - mechanism of action?

Answer 13

selectively inhibits the pyrophosphatase binding site of CMV DNA/RNA polymerases & reverse transcriptase

doesn’t affect cellular polymerases

treats CMV in the immunocompromised

Question 14

cidofovir - mechanism of action?

Answer 14

selective inhibition of CMV DNA polymerase as a nucleotide analogue = reduces viral DNA synthesis

prodrug activated through phosphorylation by cellular kinases

treats CMV & HIV retinitis

Question 15

list drugs used to treat herpes viruses

Answer 15

acyclovir
ganciclovir
cidoforvir
foscarnet

Question 16

describe the issue of antiviral resistance with herpes viruses

Answer 16

herpes antiviral resistance can occur through:
- thymidine kinase mutants
- DNA polymerase mutants

if there’s thymidine kinase resistance, drugs that don’t need phosphorylation like Foscarnet & cidofovir are still effective

if there’s DNA polymerase mutants - all drugs are rendered less effective

mutants are rare as herpes virus often infects immunocompetent individuals - immune system can decrease viral presence by killing infected cells = decrease viral load = decrease chance of DNA polymerase or TK mutants

Question 17

list different types of drugs used in HIV HAART treatment

Answer 17

protease inhibitors
integrase inhibitors
fusion inhibitors
anti-reverse transcriptase inhibitors = nucleoside & non-nucleoside

drugs used in combination for HAART - prevents antiviral drug resistant HIV strains

Question 18

nucleoside reverse transcriptase (RT) inhibitors - mechanism of action?

Answer 18

synthetic analogue of nucleoside thymidine - looks like a nucleoside

viral RT incorporates drug (e.g. AZT) into viral DNA/RNA during genome replication = causes DNA chain termination = stops DNA synthesis of the viral genome

Question 19

nucleoside reverse transcriptase (RT) inhibitors - example?

Answer 19

AZT/ Zidovudine

Question 20

non-nucleoside reverse transcriptase inhibitors - mechanism of action?

Answer 20

doesn’t look like a nucleoside, but acts as a non-competitive inhibitor for HIV RT - incorporated into viral DNA/RNA by viral RT during genome replication

works synergistically with nucleoside-RT-inhibitors due to different binding mechanisms = good for preventing antiviral resistance

Question 21

non-nucleoside reverse transcriptase inhibitors - example?

Answer 21

Nevirapine

Question 22

describe pre- and post-exposure prophylaxis treatment for HIV

Answer 22

pre-exposure - PEP treatment within 72 hours of exposure
- nucleotide RT inhibitors & integrase inhibitors used in combination

post-exposure - PrEP treatment to block transmission
- nucleotide RT inhibitors & combination of other drugs/ analogues

Question 23

describe resistance of antivirals with HIV

Answer 23

selection pressure from drug presence and naturally high mutation frequency & viral load with HIV = high chance of resistance strains

an infected person will often have a quasi-species of HIV within their system = multiple HIV genome types with different genome content, creates a viral swarm

highly likely for a antiviral resistant strain to be present in an infected person

Question 24

why does HIV have a high mutational rate?

Answer 24

HIV RT doesn’t have a proof-reading capacity - makes lots of errors whilst replicating viral RNA to DNA = lots of viral mutants produced

creates many quasi-species/ viral swarm of multiple different HIV genome types within one infected person

Question 25

list antiviral drugs used to treat influenza

Answer 25

amantadine
zanamivir
oseltamivir/ Tamiflu

Question 26

amantadine - mechanism of action?

Answer 26

inhibits influenza viral uncoating - rarely used nowadays as there’s a lot of resistance mutations

Question 27

zanamivir oseltamivir - mechanism of action?

Answer 27

inhibits virus release from infected cells by inhibiting neuraminidase interaction with the cell surface

inhibits neuraminidase at a highly conserved site to reduce chances of mutational resistance

Question 28

describe influenza resistance to antivirals

Answer 28

a single amino acid change can cause complete resistance to an antiviral influenza drug

likely to be selected from among quasi-species during treatment - more transmissible and virulent with resistance

Question 29

drugs used to treat Hep C?

Answer 29

ribavirin
direct acting antivirals/DAAs

Question 30

features of Hep C

Answer 30

transmitted by blood, common in drug users & occupational risk infection with potential needle-stick injuries

causes chronic liver disease

vaccination isn’t available

Question 31

ribavirin - what is it? mechanism of action against Hep C?

Answer 31

nucleoside analogue

delivered into infected cells in inactive form - activated to ribavirin phosphate = causes DNA chain termination of Hep C viral replication

no RNA produced = no viral replication = no viral disease transmission

Question 32

disadvantage of ribavirin?

Answer 32

easy to get antiviral resistance mutations against this drug with Hep C

Question 33

DAAs - mechanism of action for treating Hep C?

Answer 33

targets specific steps in the HCV viral life cycle - different DAAs target specific HCV enzymes or proteins/ steps

1. NS3/4 protease inhibitors = inhibit translation and polyprotein processing of viral RNA
2. NS5B polymerase inhibitors = inhibits viral replication
3. MS5A inhibitors = blocks assembly of viral proteins into virions

different drugs with different targets can be used synergistically in combination

Question 34

advantage of DAAs in treating Hep C?

Answer 34

different drugs within DAAs target different steps within the HCV life cycle - can be used synergistically

targets HCV specifically - shortens length of therapy, minimises side effects

works well over time with improved sustained virologic response rate

Question 35

describe the occupational infection hazards with viruses - how is this managed?

Answer 35

sharp injuries, needle-stick injuries transmitting blood-borne viruses, splashes of contaminated blood/ saliva

prevention through gloves, eye wear, protective wear

management with post-exposure prophylaxis specific to different viruses - more effective if it’s rapidly given and at sufficient strength

Question 36

post-exposure prophylaxis for Hep B?

Answer 36

specific Hep B Ig vaccine provides passive immunity within 48 hours

Question 37

post-exposure prophylaxis for Hep C?

Answer 37

interferon-gamma and ribavarin for 6 months within the first 2 months of exposure

Question 38

post-exposure prophylaxis for HIV?

Answer 38

antiviral drug treatment with nucleoside-RT-inhibitors and a protease or integrase inhibitor

Question 39

examples of viral infections with no effective therapies?

Answer 39

rabies
dengue
common cold viruses
Ebola
HPV