HIV Antivirals - MCMP Flashcards
What drug is this?
tenofovir
NRTI
What drug is this?
emtricitabine
NRTI
What drug is this?
abacavir
NRTI
What drug is this?
lamivudine
NRTI
How are nucleoside reverse transcriptase inhibitors (NRTIs) activated before enzyme inhibition can take place?
abacavir
emtricitabine
tenofovir alafenamide
lamivudine
Must be activated by host cellular kinases to triphosphate form
Why does tenofovir have a longer half-life compared to the other NRTIs?
Consider differences in structure and activation
- It is a nucleotide analog – it only requires two phosphorylations to become active wherease the other NRTIs are nucleoside analogs that require three phosphorylations.
- It is bypassing the first phosphorylation – which is rate limiting for the others.
- tenofovir is a deoxyadenosine analog
- It doesn’t have a ribose ring
What are the side effects of tenofovir?
- nephrotoxicity
What is the role of the HLA-B*5701 polymorphism?
- causes hypersensitivity rxn to abacavir
How can HIV become resistant to the NRTIs? How is resistance managed?
- RT inhibitors are unable to suppress 100% of viral replication
- large amounts of virus = more mutations
- use drugs in combination!
What are the ideal combinations of NRTI inhibitors?
Used in combo to increase efficacy
- tenofovir + emtricitabine
- abacavir + lamivudine
TEAL
How do the non-nucleoside RT inhibitors inhibit reverse transcriptase?
- In the presence of NNRTI, nucleoside triphosphate and template bind tightly to RT but not productively
- This blocks polymerization
Where do the non-nucleoside RT inhibitors bind to RT? What are the consequences of binding?
- Bind directly to site on RT – hydrophobic pocket near catalytic site
- binding affects flexibility of enzyme –> slows down and inhibits activity of RT
How does HIV become resistant to non-nucleoside RT inhibitors?
- Single mutation in binding site can promote resistance
How do integrase inhibitors inhibit HIV integrase?
bictegravir, dolutegravir, elvitegravir
Integrase inhibitor block the strand transfer step.
Integrase function: Inserts HIV DNA into host cell DNA via two steps: 3’ processing and strand transfer
What is the key structural feature of the HIV integrase inhibitors that enables them to inhibit HIV integrase?
bictegravir, dolutegravir, elvitegravir
The oxygens within the drugs structures coordinate the metal ion that integrase uses to catalyze insertion. This blocks the strand transfer.
What drug is this?
atazanavir
PI
What drug is this?
darunavir
PI
What drug is this?
tipranavir
Non-peptidomimetic PI
What is the mechanism by which protease inhibitors block HIV protease activity?
- amide bond is replaced by non-cleavable linkages
- inhibitor binding causes a conformation change in protease – “flaps” close
How does resistance to protease inhibitors arise?
- mutations can be in active site or far away
- most occur in or near substrate cleft of protease
How do darunavir and atazanvir differ from other protease inhibitors with regards to PI resistance mutations?
- Darunavir hydrogen-bonds with the peptide backbone so it is less affected by changes in amino acid side chains
- Darunavir can inhibit both wildtype and mutants that are resistant to other PIs
- retains activity against most-PI resistant proteases
How can the effect of protease inhibitors on CYP3A4 be exploited for anti-retroviral therapies?
- PI Boosting
- increases serum concentrations
- tipranavir used with ritonavir
- reduces emergence of resistant viruses
What is the recommended initial anti-retroviral drug regimen?
- darunavir
What are the unique features of darunavir?
- makes extensive hydrogen bonds with protease backbone
- inhibits HIV protease dimerization
