Anti-virals Flashcards
What was the leading cause of death is the US during the early 90’s?
HIV/AIDS
What was the game changer developed in the 90s to curb HIV/AIDS mortality rate?
triple therapy
What was the HIV/AIDS treatment before 1993? After?
before = monotherapy (primarily nucleoside inhibitors)
after = triple therapy with protease inhibitors
What are some obvious HIV-1 targets?
- RT
- integration
- maturation and assembly requires viral protease
What does Mg2+ in viral polymerases do?
aligns primer and incoming NT
What properties should nucleotide analogues have to inhibit viral polymerases?
- allow incorporation
- block next steps
Which was the first anti-HIV drug?
AZT
What nucleoside does AZT resemble, how is it different? What is the effect of this difference?
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
Why aren’t anti-HIV dugs not cures?
once the genome is integrated you cannot cure it
- resevoir
-if patient stops therapy, HIV rebounds quickly
What is the CCR5 delta32 mutation?
- naturally occuring mutation
- inhibits HIV entry
How was the Berlin patient cured of HIV?
- patient had HIV and cancer
- patient had chemotherapy and radiation to wipe out their immune system
- patient received stem cell transplant from a donor that is homozygous for the CCR5 delta32 mutation
- cured of HIV
How can we reactivate resevoir HIV?
- HIV lives within chromatin
- if chromatin becomes acetylated, then the genes will be transcriptionally active
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
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
Describe how well combination therapy of HCV with peg-IFN and ribavirin worked?
patients did not respond well (non-responsive and relapse)
What are some properties of ribavirin?
- 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)
What are the four proposed mechanisms of ribavirin?
- decreases the pool of available NTs
- inhibits rdRNAP (RdRp)
- mutagen -> forces virus into error catastrophe
- effects immune system -> immune response to virus
What kind of analog is ribavirin?
A and G analog (base pairs with C and U)
Which drug was a game changer of HCV treatment?
DAA = protease inhibitor
What are the steps in drug discovery?
- understand how the virus works
- understand the enzymes required for replication and entry
- identify targets
Why does drug-resistance occur is HCV?
- 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
How can drug-resistance be curbed in HCV?
- multi-drug therapies
- resistance is minimized with perfect use of drug regimen
What kind of drug is Sovaldi/sofosbuvir/SOF?
nucleoside analogue
How is resistance to SOF generated and curbed?
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
Why don’t we have drugs available for emerging viruses/ why don’t we prepare well for pandemics?
Because pandemics are unpredictable pharmaceutical companies do not waste time and resources to produce drugs that may not be relevant
