Anti-HIV Drugs

Question 1

what kind of anti-HIV drugs are fostemsavir and enfuvirtide?

what kind of anti-HIV drugs are ibalizumab and maraviroc?

Answer 1

fostemsavir and enfuvirtide: viral entry inhibitors, virus targeting

ibalizumab (CD4) and maraviroc (CCR5): viral entry inhibitors, human targeting

Question 2

what kind of anti-HIV drugs are emtricitabine, tenofovir disoproxil, doravirine, and tenofovir alafenamide?

which of these is different from the others?

Answer 2

all RT inhibitors

nucleoside: emtricitabine, tenofovir disoproxil, tenofovir alafenamide

non-nucleoside: doravirine

Question 3

what kind of anti-HIV drugs are bictegravir, raltegravir, and dolutegravir?

Answer 3

viral integrase inhibitors - inhibit integration of viral DNA into cellular genome

Question 4

what kind of anti-HIV drug is darunavir?

Answer 4

protease inhibitor

Question 5

describe the sequence of events necessary for HIV entry into host cell

Answer 5

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

Question 6

provide the following information for Fostemsavir, an anti-HIV drug blocking viral entry:
a. mechanism
b. metabolism
c. administration
d. use

Answer 6

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)

Question 7

what kind of drug is Fostemsavir? How is it metabolized, and what is the clinical significance of this?

Answer 7

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)!

Question 8

why are oral anti-HIV drugs preferable?

Answer 8

easier to take —> better medication adherence, especially considering patients with HIV are often taking many medications

Question 9

which anti-HIV drug targets human cells, and how does it work?

Answer 9

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!

Question 10

what kind of drug is Ibalizumab, how is it administered, and how does it work?

Answer 10

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

Question 11

how do nucleoside reverse transcriptase inhibitors (NRTI) work? (anti-HIV drugs)

Answer 11

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

Question 12

why must NRTIs (nucleoside RT inhibitors, anti-HIV drugs) be given as prodrugs?

Answer 12

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

Question 13

what kind of drug is Emtricitabine, and what special feature does it have that extends its half life?

Answer 13

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

Question 14

what kind of drug is Tenofovir disoproxil, and what is different about this drug compared to others in its class?

Answer 14

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

Question 15

____ + _____ = Truvada

Answer 15

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

Question 16

what are the adverse effects of Tenofovir disoproxil, an anti-HIV NRTI (but actually a nucleTIDE,not nucleoside)

Answer 16

nephrotoxicity and decrease in bone mineral density

Question 17

contrast tenofovir disoproxil to tenofovir alafenamide

Answer 17

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]

Question 18

describe how NRTIs (anti-HIV drugs) can cause potentially fatal lactic acidosis

Answer 18

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

Question 19

how do non-nucleoside RT inhibitors (NNRTIs, anti-HIV drugs) work?

Answer 19

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

Question 20

what kind of drug is doravirine, and what advantage does it have over older drugs in its class?

Answer 20

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)

Question 21

what kind of drug is Bictegravir and how does it work?

Answer 21

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

Question 22

what kind of drug is darunavir and how does it work? what are its advantages compared to older drugs of this class?

Answer 22

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)

Question 23

what are the clinically significant pharmacodynamics of darunavir (anti-HIV protease inhibitor)? (2)

Answer 23

darunavir -

1. inhibitor and substrate of CYP3A
2. can be taken with cobicistat to reduce P450 clearance to increase half-life

Question 24

describe how anti-HIV protease inhibitors are selective for HIV protease

Answer 24

HIV protease is a dimer

human protease is a monomer

Question 25

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

Answer 25

protease inhitors

“latest/greatest”: Darunavir (smaller than older PI, can withstand mutations in protease)

Question 26

what are 3 important parameters to consider when co-formulating anti-HIV drugs?

Answer 26

1. few overlapping toxicities
2. no overlapping resistance profiles
3. comparable pharmacokinetics (similar half-lives)