HIV drugs Flashcards
o resistance - change in AA of gp41
o binds gp41 to prevent conformational change needed for binding to CCR5 or CXCR4 - virus can no longer enter
o injection administration - not a first line drug for this reason
Fusion inhibitors
o inhibits CCR5 R → virus can’t bind and can’t enter cell
o If virus uses CXCR4 the drug will not function - can be a form of resistance
o would need to do tropism testing in order to determine if the virus is using CXCR4 rather than CCR5
Chemokine receptor inhibitors
o pro-drug → phosphorylated into active form → inhibit RT or incorporate into viral DNA as it is being made →inhibit production of the dsDNA
o host cellular enzyme does the phosphorylating - the enzyme converting nucleoside to nucleotides
o competitive inhibitor
o Occurring in cytosol (where reverse transcriptase is)
NucleoSide reverse transcriptase inhibitors
o Nucleotide has been phosphorylated
o Skip first step of nucleoside reverse transcriptase inhibitors
o Need to do some more phosphorylating (drug is a monophosphate)
NucleoTide reverse transcriptase inhibitors
o Bind directly to reverse transcriptase but at different site than NRTI
o Don’t need to be phosphorylated to be active
o Allosteric inhibitor - binds and stops the reverse transcriptase
o If HIV becomes resistant to NRTI, it might not have resistance to these because they function in different places
non-nucleoside reverse transcriptase inhibitors
o works in the cytosol (maybe the nucleus)
o blocks integrase to prevent forming the pro-virus
integrase inhibitors
o Inhibits cleaving of polyprotein - needed for survival
o bind the active site of the protease
o cannot splice gag-pol-env polyprotein → proteins cannot be used → virus cannot be infectious
o does nothing for the cell that is infected already - does not inhibit the provirus
cell can cause apoptosis of other CD4+ T cells, but no virus particle production occurs
protease inhibitors
o prevents metabolism of other protease inhibitors to promote their concentration in the blood
called a “booster”
used in conjugation with other protease inhibitors
Ritonavir
Why are drugs used in combination?
o Reverse transcriptase makes a lot of mistakes - high mutation rate
o Typically use triple cocktail of different classes of drugs
o AZT used in combination now because of this high rate of mutation - want to prevent resistance
reason AZT is no longer used alone
Toxicities of NRTIs:
- mitochondrial toxicity and lactic acidosis
Toxicities of Non-NRTIs/
- rash, GI, drug interactions
Toxicities of protease inhibitors?
o Drug interactions
o Peripheral lipoatrophy and central fat accumulation = fat distribution
skinny arms and a fat gut
Whats the difference between nucleosides and nucleotides?
nucleotides have one or more phosphate groups
nucleoSide = Smaller (no phosphates)
4 nucleoside reverse transcriptase inhibitors:
Zidovudine (Azidothymidine or AZT)
Lamivudine
Emtricitabine
Abacavir
Side fx:
- granulocytopenia and anemia in up to 45% of treated patients (hematological monitoring at 2 week intervals).
- CNS disturbances: severe headache, nausea, insomnia, malaise
Zidovudine (Azidothymidine or AZT)
