Anti-HIV Drugs Flashcards
what kind of anti-HIV drugs are fostemsavir and enfuvirtide?
what kind of anti-HIV drugs are ibalizumab and maraviroc?
fostemsavir and enfuvirtide: viral entry inhibitors, virus targeting
ibalizumab (CD4) and maraviroc (CCR5): viral entry inhibitors, human targeting
what kind of anti-HIV drugs are emtricitabine, tenofovir disoproxil, doravirine, and tenofovir alafenamide?
which of these is different from the others?
all RT inhibitors
nucleoside: emtricitabine, tenofovir disoproxil, tenofovir alafenamide
non-nucleoside: doravirine
what kind of anti-HIV drugs are bictegravir, raltegravir, and dolutegravir?
viral integrase inhibitors - inhibit integration of viral DNA into cellular genome
what kind of anti-HIV drug is darunavir?
protease inhibitor
describe the sequence of events necessary for HIV entry into host cell
gp120 undergoes conformational change to bind CD4, which induces another conformational change to bind CCR5/CXCR4
binding receptor causes gp120 to release gp41, which uncoils and hooks cell membrane to reel it in
cell and viral membranes fuse at close proximity
provide the following information for Fostemsavir, an anti-HIV drug blocking viral entry:
a. mechanism
b. metabolism
c. administration
d. use
a. mechanism: binds gp120, blocking conformational change necessary to bind CD4
b. metabolism: prodrug, metabolized to temsavir, cleared by CYP3A4 (beware of co-administration with inducers such as rifampin!)
c. administration: oral
d. use: multi-drug resistant HIV (newly approved, reserved for when older options stop working)
what kind of drug is Fostemsavir? How is it metabolized, and what is the clinical significance of this?
Fostemsavir: anti-HIV drug, viral entry inhibitor (binds gp120)
prodrug - metabolized to temsavir
**cleared by CYP3A4 - beware of co-administration with inducers such as rifampin (RIF)!
why are oral anti-HIV drugs preferable?
easier to take —> better medication adherence, especially considering patients with HIV are often taking many medications
which anti-HIV drug targets human cells, and how does it work?
Ibalizumab: viral entry inhibitor
binds CD4:gp120 complex - blocks docking with co-receptor (CXCR4 or CCR5)…
thereby blocking gp120 from undergoing its next conformational change which is necessary to release gp41 (needed for viral fusion)
*note it does not affect normal CD4 activity because it only binds the conformation it is in with gp120!
what kind of drug is Ibalizumab, how is it administered, and how does it work?
Ibalizumab: anti-HIV mAb targeting human CD4:gp120 complex, preventing docking with co-receptor and therefore viral entry
via IV infusion every 2 weeks (in combination - note that anti-HIV drugs are never given in isolation)
used for multi-drug resistant HIV
how do nucleoside reverse transcriptase inhibitors (NRTI) work? (anti-HIV drugs)
nucleoside analogs that do not have 3’-OH necessary for growing DNA chain —> act as chain terminators
“suicide substrates” that poison RT chain elongation, bind active site of HIV RT
selective for RT because they do not bind well to nuclear DNA pol
*note that NRTIs prevent acute infection but have little effect on infected cells
why must NRTIs (nucleoside RT inhibitors, anti-HIV drugs) be given as prodrugs?
NRTIs are nucleoside analogs without 3’ hydroxyl group, thereby blocking RT-mediated DNA elongation
recall that in DNA synthesis, 3’-OH attacks alpha phosphate of a dNTP (deoxy-nucleotide phosphate)
if drugs came as triphosphates, the excess charge would prevent transport into the cell - instead, they are converted to triphosphates by host enzymes, and phosphorylation traps drug inside the cell
what kind of drug is Emtricitabine, and what special feature does it have that extends its half life?
Emtricitabine: anti-HIV drug, NRTI (nucleoside RT inhibitor)
contains fluorine atom that makes it harder for the drug to be degraded —> extended half life, can be taken orally 1x/day
what kind of drug is Tenofovir disoproxil, and what is different about this drug compared to others in its class?
Tenofovir disoproxil: anti-HIV drug, NRTI (nucleoside RT inhibitor) except that it’s actually a nucleotide
hides triphosphate with protective group so it can still get into cell, thereby overcoming rate limiting phosphorylation step within the cell
protective groups stripped in plasma before transport
acts as chain terminator because it lacks 3’OH
*note adverse effects of nephrotoxicity and decrease in bone mineral density
____ + _____ = Truvada
emtricitabine + tenofovir disoproxil = Truvada (anti-HIV drug combo, both NRTIs - chain terminators)
emtricitabine: F atom increases t1/2
tenofovir disoproxil: actually a nucleotide, protective groups (stripped in plasma) hide triphosphate - overcomes rate-limiting phosphorylation step within cell
what are the adverse effects of Tenofovir disoproxil, an anti-HIV NRTI (but actually a nucleTIDE,not nucleoside)
nephrotoxicity and decrease in bone mineral density
contrast tenofovir disoproxil to tenofovir alafenamide
both anti-HIV nucleoTIDE RT inhibitors (chain terminators), use protective groups to hide triphosphate charge (for entry into cell)
tenofovir disoproxil: protective group stripped in plasma
tenofovir alafenamide: protective groups removed after entry into cell (easier entry), same efficacy can be achieved at lower levels with fewer side effects!
[recall that adverse effects include nephrotoxicity and decrease in bone minerals]
describe how NRTIs (anti-HIV drugs) can cause potentially fatal lactic acidosis
NRTIs (nucleoside RT inhibitors) are selective to HIV RT because they do not bind well to nuclear DNA pol
however, mitochondria polymerases are less selective than nuclear pol, so high drug levels can poison mitochondria —> lactic acidosis
how do non-nucleoside RT inhibitors (NNRTIs, anti-HIV drugs) work?
NNRTIs fill binding pocket adjacent to RT active site, act as allosteric inhibitors (induce conformational change that blocks RT activity)
*note NNRTIs interact with P450 CYP3A4 (either inhibit or induce)
ex: Doravirine
what kind of drug is doravirine, and what advantage does it have over older drugs in its class?
doravirine: anti-HIV NNRTI (non-nucleoside RT inhibitor), allosteric inhibitor of RT
more flexible than older NNRTIs (higher affinity with minimal contact points, allowing it to bind to mutated binding pockets)
effective at lower concentrations
*note doravirine is metabolized by CYP3A4
DORA is exploring for alternative binding sites! (besides active site)
what kind of drug is Bictegravir and how does it work?
Bictegravir: anti-HIV drug, viral integrase inhibitor
bind Mg2+ in integrase:DNA complex, displaces terminal nucleotide from active site - stalled integrating DNA is degraded
*does not interfere with initial 3’ processing of viral DNA, but displaces the 3’OH ends from active site
taken in combo pill, for treatment naive patients
what kind of drug is darunavir and how does it work? what are its advantages compared to older drugs of this class?
darunavir: anti-HIV protease inhibitor - blocks proteolytic cleavage of viral polyproteins
transition state analog, binds reversibly, no cross rxn with human proteases (human proteases are monomers, HIV protease is dimer)
advantages: higher affinity, smaller (not displaced by mutations in protease which protrude into active site)
what are the clinically significant pharmacodynamics of darunavir (anti-HIV protease inhibitor)? (2)
darunavir -
- inhibitor and substrate of CYP3A
- can be taken with cobicistat to reduce P450 clearance to increase half-life
describe how anti-HIV protease inhibitors are selective for HIV protease
HIV protease is a dimer
human protease is a monomer
what class of anti-HIV drugs exhibit the following pharmacodynamics:
- administered orally but have low bioavailability
- metabolized by P450 CYP3A4 in liver and intestinal epithelial cells
- substrates for multidrug efflux pumps, limiting intracellular concentration
- high binding to plasma proteins
protease inhitors
“latest/greatest”: Darunavir (smaller than older PI, can withstand mutations in protease)
what are 3 important parameters to consider when co-formulating anti-HIV drugs?
- few overlapping toxicities
- no overlapping resistance profiles
- comparable pharmacokinetics (similar half-lives)
