Antiviral 2 - HIV Flashcards
1
Q
Understand what is meant by genetic barrier to resistance.
A
Individual NRTIs have a low genetic barrier to resistance which means there is a high risk of mutations that can overcome therapy and this is why we use combination therapy for treatment of HIV
2
Q
Be able to explain how nucleoside RT inhibitors are activated metabolically before enzyme inhibition can occur.
A
- Work by blocking 2 parts: block RNA dependent DNA polymerase and DNA dependent DNA polymerase
- NRTIs act as competitive inhibitors of reverse transcriptase and work as DNA chain terminators
- ALL ARE PRODRUGS – all of these use cellular enzymes to be phosphorylated whereas treatment of herpes they use viral enzymes to be phosphorylated
- Competes with endogenous bases and want to outcompete them so the ratio of NRTIs to dNTPs is important
3
Q
NRTI drugs
A
- Abacavir
- Emtricitabine
- tenofovir alafenamide
- lamivudine
4
Q
- Be able to recognize the structures of tenofovir, emtricitabine, abacavir, and lamivudine.
A
- Tenofovir does not have ribose ring, don’t have ability to form phosphodiester bonds
- Lamivudine and emtricitabine the sugar ring mimic have a sulfur present
- Abacavir has a double bond on the 5 ring and a triangle at the top
- Variation in structure changes the hydrogen bonding in the DNA strand
5
Q
- Be able to discuss the differences in structure and activation between tenofovir and the other nucleoside RT inhibitors. How does this contribute to the longer half-life of tenofovir?
A
- Phenol and isopropyl ester protecting the phosphonate that will get cleaved by host to liberate tenofovir ONLY in the viral cell and thus getting phosphorylated twice
- TAF is very stable in the plasma and really only becomes active in the target viral cells
6
Q
- Be able to explain the activation pathways for tenofovir alafenamide and tenofovir side effects.
A
- The phenol and isopropyl esters will get cleaved by host enzyme only in viral cell which will lead to 2 phosphorylation steps that lead to activation of the drug and because of these changes in structure it is much more active towards viral cells and is more stable in plasma leading to less risk of kidney toxicity
- Must be processed to TFV by cellular enzymes before phosphorylation steps
- Side effects: due to small affinity to mitochondrial toxicity which leads to peripheral neuropathy, anemia
7
Q
- Be able to discuss the hypersensitivity reaction caused by abacavir in some patients. Be able to describe the role of the HLA-B*5701 polymorphism
A
- Black box warning of hypersensititve reaction
- Patients should be genotypes before starting therapy
- Testing for the HLA-B 5701 – if patient has this it means they are at risk of this hypersensitivity reaction
8
Q
- Be able to describe how HIV can become resistant to the RT inhibitors. Does resistance to one RT inhibitor confer resistance to all drugs in this class? How can combinations of RT inhibitors be used to manage resistance?
A
- Discriminatory mutation: enzyme due to single residue change is now discriminating towards the NRTI vs host base – this mutation helps the reverse transcriptase distinguish between normal dNTPs and NRTIs
- Excision mutation: This is when the HIV reverse transcriptase has mutated to be able to remove the NRTI that has been incorporated into the DNA chain (this requires ATP molecule) – ATP and RT can together remove the NRTI that was incorporated into chain
9
Q
- Be able to describe how the non-nucleoside RT inhibitors inhibit RT.
A
- Inhibit reverse transcriptase and bind on reverse transcriptase at a hydrophobic pocket near the active site, the binding of NNRTIs affects the flexibility of the reverse transcriptase which leads to slowing down of its activity
- NNRTIS do NOT compete with nucleotides and DO NOT need to be phosphorylated
- Block RNA and DNA dependent DNA polymerase activity
- Not incorporated into DNA strand
10
Q
- Be able to describe where the non-nucleoside reverse transcriptase inhibitors bind to RT, and what the consequences of the binding are.
A
- MOA: bind to allosteric site and cause confirmation change of the active site
- Consequences of this binding is that a single mutation in the binding site can promote resistance
11
Q
- Be able to state in general how HIV becomes resistant to the non-nucleoside RT inhibitors
A
- Mutation in the hydrophobic allosteric site can lead to resistance and decreased affinity of binding
- Mutations happen right at the NNRTI binding site
- NNRTI mutations that cause resistance do not lead to resistance to NRTIs
12
Q
Integrase inhibitors (INI)
* Be able to describe the mechanism by which bictegravir, dolutegravir, and elvitegravir inhibit HIV integrase. - exam q
A
- Integrase inhibitors work by chelating the 3 metal ions and which stabilizes the enzyme DNA complex and blocks strand transferring of HIV DNA to human genome
- Integrase takes HIV DNA and incorporates it into the human cell (this is something we do not have in human cells)
- These inhibitors work to inhibit the insertion of HIV DNA into the human genome
- INIs work by blocking the strand transfer step
- Integrase uses divalent metal ions to catalyze insertion
13
Q
- Be able to explain the key structural feature of the HIV integrase inhibitors that enables these compounds to inhibit HIV integrase? - exam Q
A
- Use different oxygen molecules in the drug structure to coordinate the metal ion and stall the integrase activity
- Use the oxygen molecules to coordinate the 3 metals that are essential for blocking strand transfer
14
Q
- Be able to recognize the structure of HIV protease inhibitors atazanavir and darunavir, and identify the non-cleavable bonds. How does the structure of tipranavir, a non-peptidomimetic PI, differ?
A
- Darunavir can make extensive hydrogen bonds with protease backbone and inhibits HIV protease dimerization which is essential for activity
- Tipranavir is a non-peptidomimetic so it does not mimic the substrate and it retains activity against protease resistances that the others cannot
15
Q
- Be able to discuss the mechanism by which protease inhibitors block HIV protease activity.
A
- Normal HIV protease has a dimeric active site that can cleave its own poly protein to become a mature and infective virus
- Peptidomimetics work by mimicing the peptide bonds that protease usually cleaves but does not have the amide bond. when binding to protease it induces a conformational change that closes the “flap” of protease and blocks its ability to cleave the polyprotein
- Amide bond is replaced by non-cleavable linkages so the protease cannot cleave the bond
- Binding to the active site causes the flaps of the active site to close and now the protease cannot cleave gag-pol
16
Q
- Be able to describe how resistance to protease inhibitors arises, and how the development viral strains that are resistant to protease inhibitors can be minimized. How do darunavir and atazanvir differ from other protease inhibitors with regards to PI resistance mutations?
A
- Mutation can be in active site or allosteric both with modulate and reduce affinity
- V82A mutation reduces affinity of protease so it reduces activity of peptidomimetic inhibitors
- Darunavir and tipranavir retain activity against most activity
- I50L mutation confers resistance to atazanavir but increases susceptibility to other PIs – Can use a different drug in the same class***
17
Q
- Be able to describe how the effect of protease inhibitors on CYP3A4 can be exploited for anti-retroviral therapies (i.e., what is PI-boosting and how is it used?). - exam q
A
- All are substrates or inhibitors on CYP3A4 which means high potential of drug interaction
- Levels of PI can be influenved with other CYP
- Ritonavir inhibit CYP3A4 and can boost levels of PIs and make sure its high enough concentrations to inhibit the protease
18
Q
- Be able to describe why the structures of ritonavir and cobicistat act on CYP3A4 to act as PI boosters. - exam q
A
These work to decrease metabolism of the drugs so that the concentration remains above the MIC, and we can ensure that the drug is effective for the patient
19
Q
- Be able to state the currently recommended initial anti-retroviral drug regimen.
A
- Biktarvy (INI and 2 NRTIs) Bictegravir, emtricitabine and tenofovir
- Triumeq (INI and 2 NRTIs) Dolutegravir, abacavir and lamivudine
- Dovato (INI and NRTI) Dolutegravir and lamivudine
- Genvoya (INI and 2 NRTIs) – elvitegravir/cobicistat, emtricitabine and tenofovir
