Dr. Stahelin HIV Flashcards
Genetic barrier of resistance
the number of mutations in an antiretroviral therapeutic target that are required to confer a clinically meaningful loss of susceptibility to that drug
Maraviroc
- HIV entry inhibitor
- selective human CCR5 antagonist. Binds to CCR5 on human cells and causes a conformational change that prevents gp120 binding.
- Has no effect on cell surface levels on CCR5 or on CCR5 signaling
- can only be used in patients with HIV strains that utilize CCR5
Enfuviritide
- Fusion inhibitor
- binds to HIV GP41 and blocks GP41 conformation change needed for fusion.
- 36 amino acid peptide that inhibits fusion of virus membrane with cell membrane
- only active against HIV-1
NRTI
- are nucleoside analogs that lack the 3’ OH (sometimes called false nucleotides)
- 2 effects: competitive inhibitor of RT and DNA chain terminator to inhibit elongation. They do this by blocking endogenous nucleotides from being formed.
- interfere with 1st and 2nd strand DNA synthesis
- active against HIV-1 and HIV-2
NNRTI
- bind directly to site on RT- hydrophobic pocket near the catalytic site but distinct from that of NRTIs. This binding affects the flexibility of enzyme NNRTIs DO NOT COMPETE with nucleotides for binding (non-competitive inhibitors)
- block RNA and DNA-dependent DNA polymerase activities
- blocks polymerization
Integrase inhibitors
inhibits the insertion of HIV DNA into the human genome by blocking the strand transfer step.
Protease inhibitors
Protease inhibitors are transition state mimetics that can be peptidomimetic (unable to be cleaved) or non-peptide mimetic that work by binding to proteolytic enzymes and blocking their ability allow maturation of the budding HIV particle.
How NRTIs are activated metabolically before enzyme inhibitor can occur
all NRTIs must be activated by cellular kinases to triphosphate forms (or equivalent) to be picked up by DNA polymerases. They compete with endogenous nucleotides for DNA polymerase.
structural differences of endogenous nucleosides and nucleoside analogs used in NRTIs
Nucleosides contain a 3’ OH group on the sugar backbone. NRTIs lack a 3’ OH is replaced with sulfur, double bond, no additional group, or like tenofovir acyclic structure. And can have additional moieties/functional groups in the nucleotide group such as fluorine or tricyclic ring.
Activation of Tenofovir and differences in structure compared to other NRTIs and how this effects half life.
-tenofovir disoproxilfumarate (TDF) is a pro-drug that is converted into tenofovir (TFV). It is an acyclic nucleoside phosphonate analog of adenosine that requires 2 phosphorylation steps instead of 3. Its phosphonate group cannot be cleaved by cellular esterases making it catabolically stable and causing a longer intracellular half-life.
TAF advantages over TDF
- lower plasma concentrations
- increased accumulation in lymphocytes
- fewer side effects
- better accumulation in lymph nodes and higher intracellular concentrations
Why tenofovir and emtricitabine are preferred NRTIs for initial ART
- TFV has a long intracellular half-life
- once-daily dosing
- equivalent efficacy to other NRTI combinations
- less fat maldistribution
- different resistant mutation profiles
Hypersensitivity reaction caused by Abacavir
- potentially fatal hypersensitivity reaction
- symptoms: malaise, dizziness, headache, GI disturbances
- highly associated with HLA-B*507 allele, and testing for this polymorphism is recommended before initiating treatment with abacavir
Resistance to RT inhibitors
- Discriminatory and excision mutations
- mutations are mainly near the RT active site but can occur at more distant locations
- mutations can either help RT to distinguish between normal dNTPs or NRTIs or promote the removal of NRTIs after they’ve been incorporated into the growing chain.
- individual NRTIs have a low barrier of resistance
- some mutations confer resistance to a subset of NRTIs but make RT more susceptible to inhibition of others, this is why NRTIs are preferred in combination to take advantage of this phenomena
NNRTI mechanism of action
bind on RT at the hydrophobic pocket near the catalytic site and this binding affect the flexibility of RT and the catalytic site, thus preventing the uptake of endogenous nucleosides. NNRTIs do NOT compete with nucleotides for binding (non-competitive inhibitors)
- do not have to be phosphorylated like NRTIs
- block RNA and DNA-dependent polymerase activities
