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IMIN 324 > Anti-virals > Flashcards

Anti-virals Flashcards

1
Q

What was the leading cause of death is the US during the early 90’s?

A

HIV/AIDS

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2
Q

What was the game changer developed in the 90s to curb HIV/AIDS mortality rate?

A

triple therapy

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3
Q

What was the HIV/AIDS treatment before 1993? After?

A

before = monotherapy (primarily nucleoside inhibitors)
after = triple therapy with protease inhibitors

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4
Q

What are some obvious HIV-1 targets?

A
  1. RT
  2. integration
  3. maturation and assembly requires viral protease
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5
Q

What does Mg2+ in viral polymerases do?

A

aligns primer and incoming NT

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6
Q

What properties should nucleotide analogues have to inhibit viral polymerases?

A
  1. allow incorporation
  2. block next steps
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7
Q

Which was the first anti-HIV drug?

A

AZT

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8
Q

What nucleoside does AZT resemble, how is it different? What is the effect of this difference?

A

AZT resembles thymidine, only difference is the 3’OH -> 3’ N3

Because of this modification at the 3’ end of the sugar, subsequent NTs cannot be added -> chain termination

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9
Q

Why aren’t anti-HIV dugs not cures?

A

once the genome is integrated you cannot cure it
- resevoir
-if patient stops therapy, HIV rebounds quickly

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10
Q

What is the CCR5 delta32 mutation?

A
  • naturally occuring mutation
  • inhibits HIV entry
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11
Q

How was the Berlin patient cured of HIV?

A
  1. patient had HIV and cancer
  2. patient had chemotherapy and radiation to wipe out their immune system
  3. patient received stem cell transplant from a donor that is homozygous for the CCR5 delta32 mutation
  4. cured of HIV
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12
Q

How can we reactivate resevoir HIV?

A
  • HIV lives within chromatin
  • if chromatin becomes acetylated, then the genes will be transcriptionally active
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13
Q

Why is HCV curable unlike HIV and HBV? Describe (for each of the three viruses) the long-lived proviral resevoir, viral targets of therapy, of there is a cure with current therapy (and why), and what the current therapeutic goal is

A

HIV:
- long lived provial reservoir: YES
- viral targets: mutliple
- cure with current therapy?: NO (integrated viral DNA)
- current therapeutic goal: lifelong supression

HBV:
- long lived proviral reservoir: YES
- viral targets: one
- cure with current therapy?: NO (cccDNA)
- current therapeutic goal: lifelong suppression

HCV:
- long lived proviral reservoir: NO
- viral targets: multiple
- cure with current therapy?: YES
- current therapeutic goal: Cure or eradication of HCV

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14
Q

Describe how well combination therapy of HCV with peg-IFN and ribavirin worked?

A

patients did not respond well (non-responsive and relapse)

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15
Q

What are some properties of ribavirin?

A
  • broad spectrum
  • needs a high concentration
  • mechanism of action is very elusive (don’t like drugs where we don’t know what it’s doing)
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16
Q

What are the four proposed mechanisms of ribavirin?

A
  1. decreases the pool of available NTs
  2. inhibits rdRNAP (RdRp)
  3. mutagen -> forces virus into error catastrophe
  4. effects immune system -> immune response to virus
17
Q

What kind of analog is ribavirin?

A

A and G analog (base pairs with C and U)

18
Q

Which drug was a game changer of HCV treatment?

A

DAA = protease inhibitor

19
Q

What are the steps in drug discovery?

A
  1. understand how the virus works
  2. understand the enzymes required for replication and entry
  3. identify targets
20
Q

Why does drug-resistance occur is HCV?

A
  • HCV exists as a quasi-species
  • most resistant variants are relatively unfit and undetectable prior to therapy with current technology
  • resistant variants can be selected for during treatment
21
Q

How can drug-resistance be curbed in HCV?

A
  • multi-drug therapies
  • resistance is minimized with perfect use of drug regimen
22
Q

What kind of drug is Sovaldi/sofosbuvir/SOF?

A

nucleoside analogue

23
Q

How is resistance to SOF generated and curbed?

A

Generated:
-in the presence of drugs, viral mutations are advantageous -> resistance

Curbed:
- when resistance begins to occur, stop administering SOF -> mutation will die out and WT will return
- when the WT returns, begin treatment again with a more potent regimen (SOF + RBV) -> mutation cannot be generated again

24
Q

Why don’t we have drugs available for emerging viruses/ why don’t we prepare well for pandemics?

A

Because pandemics are unpredictable pharmaceutical companies do not waste time and resources to produce drugs that may not be relevant

25
Q

What are some drug targets against Covid-19?

A
  1. inhibition of viral/host interaction
  2. endosome maturation inhibition
  3. protease inhibition
  4. inhibition of RNA genome replication
26
Q

Is remedsivir effective against ebola?

A

No - two Ab therapies were superior to remedsivir in reducing mortality

27
Q

In in vivo studies, was remedsivir and chloroquine effective at inhibiting Covid-19?

A

Yes
- inhibits replication
- cytotoxic at 100uM

28
Q

Unlike AZT, remedsivir has a 3’ OH group, why?

A

makes sure there is phosphorylation to the triphosphate form

29
Q

In remedsivir what is the purpose of the additional groups attatched to the phosphate?

A

makes sure there’s high bioavailability

30
Q

What kind of drug is remedsivir (what does it resemble)?

A

nucleoside analog - resembles adenosine

31
Q

How does remedsivir work?

A
  1. favourable competition with ATP (efficiently incorporated - ATP/RDV-TP = 0.35)
  2. delayed chain termination at position i+3
    - chain termination is not immediate due to 3’OH
  3. steric clash between RDV and S861 prevents translocation into i+4 (due to cyano group)
  4. higher NTP concentration -> read throigh
    - reversible
    - can be deterimental to inhibition
  5. if RDV is embedded in the template this inhibits UTP incorporation opposite of RDV
32
Q

Why was remedsivir found to have little effect of Covid-19 recovery is hospitables?

A

It is an IV drug -> only administered in hospital -> if a Covid-19 patient is admitted to the hospital the drug is given too late (in the course of infection) to be useful

note: there is an effect if you treat soon enough (small window)

33
Q

What is molnupiravir? (what is it used against, what kind of drug is it, what is it’s mechanism of action)

A

Covid-19 anti-viral

nucleoside analog -> has ambigous base pairing (can base pair with A and G)

mechanim: error catastrophe -> lethal mutageneis

34
Q

Name three broad spectrum antivirals and one selective antiviral

A

broad:
- ribavirin
- molnupiravir
- remedsivir

selective:
- sofosbuvir

IMIN 324 (14 decks)

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