Gartenberg - Anti-retrovirals Flashcards
What is the steps in the viral life cycle for it to infect cells?
Basically the virus has a gp120 and a gp41 envelope proteins. The gp120 essentially acts as a mask for the gp41. Once the virus gets close enough to the target cell, the CD4 or CCR5 removes the gp120 from the gp41 and allows it to do its thing. Once the gp120 is removed, the gp41 can fold onto itself and cause fusion with the target cell. Once there is fusion, the integrase, protease, and reverse transcriptase are spit out into the target cell.
Fusion inhibitors
Not really used anymore. But if you remember, gp120 is removed from the gp41 protein to allow gp41 tot fold onto itself and do its thing. Fusion inhibitors basically bind to the surface at a site that normally be occupied when the protein folds onto itself.
Enfuvirtide
- fusion inhibitor
- require subcutaneous injection twice a day, which people didn’t like. The injections also caused skin reactions at the site of injection.
Maraviroc
if you think about it, you need the receptors on the target cell surface to remove gp120 and to allow for fusion of the virus with the target cell. This drug masks CCR5 so that the drug will not be able to fuse properly.
- only works for CCR5 not CCR4
- you can use PCR to figure out which kind you have.
- HIV virus can mutate from CCR5 to CCR4 so it might not work anymore
- drug is metabolized by P450 enzymes
If Reverse transcriptase looks like a hand, where does the DNA reside
In the palm
Nucleoside reverse transcriptase inhibitors (NRTIs)
- mechanism
- pharmacodynamics
- adverse reactions
- resistance
- act as suicide substrate by poisining RT chain elongation. It does this because they are nucleoside analogs that lack the 3’ OH so nothing can be added once they are incorporated.
- selectivity because cellular DNA polymerases know that this is bad DNA so they stay away. Viral reverse transcriptase isn’t as selective and will incorporate it anyway.
- mitochondrial polymerases also aren’t as selective so patients can have mitochondrial issues that lead to lactic acidosis.
- NRTIs are pro drugs in that they must be triphosphorylated by cytoplasmic enzymes.
- resistance is due to mutations in the RT active site.
Conversion of NRTI pro drugs to nucleotide triphosphates
NRTIs are pro drugs because they lack some or all of the phosphates necessary for DNA synthesis.
- because they are initially not charged, they are able to enter the cell. Then, when inside the cell they are converted to triphosphates by host enzymes.
- phosphorylation traps the drug inside of the cell, which adds to the efficacy.
Emtricitabine
NRTI
- it is fluoridated though which allows for a longer half life. Therefore, it only has to be taken once a day.
- no P450 inderactions
Tenofovir
- tenofovir disproxyl fumarate
- tenofovir alafenamide fumarate
NRTI
- synthetic adenosine analog with a phosphate.
- the presence of the first phosphate helps overcome the rate limiting step of adding the first phosphate.
- doesn’t really interact with P450 enzymes.
- can cause nephrotoxicity (more so the first one)
Tenofovir disproxyl fumarate - protective groups are stripped before transport into the cells, which exposes the drug to every cell in the body.
Tenofovir alafenamide fumarate - never version in which they changed the protecting group so that it only goes off once it is in the lymphoid cells. Therefore, it is not toxic to other cells in the body. Also could use a lower concentration to achieve therapeutic effect.
Truvada
Combination of Emtricitabine and Tenofovir disproxyl fumarate
Descovy
Combination of Emtricitabine and Tenofovir Alafenamide fumarate
Non-nucleoside Reverse Transcriptase Inhibitors (non-NRTIs)
They block reverse transcriptase by binding to an area adjacent to the active site. Basically, it is a allosteric inhibitor.
- does not require phosphorylation because it is a pro-drug
- resistance develops rapidly so it always given with other drugs
- metabolized by P450 enzymes and either inhibit or induce P450 activity so be careful with other drugs. (A large subset of this population might be going through methodone withdrawal and need certain drugs that induce CYP3A induction.
Etravirine
NNRTI
- resistance doesn’t develop as rapidly because it can accommodate up to 3-4 mutations in the binding pocket by wiggling (bed and contort) and jiggling (reposition itself) to make a better fit.
(It used to be that they would bind very tightly so but mutations would screw everything up).
Where will you see mutations that cause resistance in NRTIs and NNRTIs
NRTI - around the active site of the polymerase
NNRTIs - outside of the pocket
HIV virus integration
Integrase cleaves 2 nucleotides off of the 3’ end of the viral DNA. This creates small overhangs and also created 3’ OHs that can readily insert themselves in the host cell genome. It then makes cuts into your DNA, inserts themselves, and then your own host cell fixes the nicks.
