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Drug Action IV > HIV (MC) - Block 3 > Flashcards

HIV (MC) - Block 3 Flashcards

1
Q

Describe the targets of HIV tx?

A
  1. Fusion/cell entry inhibitos
  2. Nucleoside/nonnucleoside reverse transcriptase inhibitors
  3. Protease inhibitors
  4. Integrase inhibitors
  5. Translation
  6. Maturation
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2
Q

What are the nitrogen bases?

A

Purine: adenine, guanine
Pyrimidine: cytosine, thymine, uracil

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3
Q

What is the difference between -side and -tide?

A

-tide contains monophosphate group

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4
Q

What prime ring on a nucleotide/side?

A

Sugar

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5
Q

Whatis AZT? MOA?

A

Ziduvudine (Azidothymine) (N=N=N)
* Gets metabolized to triphosphate which is a chain terminator

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6
Q

What is the MOA of NRTIs?

A

Targets RNA dependent DNA polymerase that transcribes single stranded RNA to double stranded DNA:
* all are chain terminators
* Competitive inhibitors

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7
Q

Structure of NRTIs?

A

2’,3’-dideoxynucleosides
* Lack 3’-OH on the deoxyribose moiety -> chain termination
* Unsaturated, hetero-substituted, carbocyclic, acyclic
* All are prodrugs that must get triphosphoralated

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8
Q

What is the rate limiting step for AZT metabolism?

A

dThd (deoxythymidine kinase)

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9
Q

Metabolism of zidovudine?

A

5’-glucuronidation

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10
Q

Describe the toxicity of zidovudine?

A

Due to inhibition of cellular polymerases:
* Bone marrow toxicity
* CNS toxicity
* Mitochondrial toxicity

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11
Q

Structure of didanosine? MOA

A

ddI: 2’-deoxyinosine

MOA: ddA triphosphate is a chain terminator

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12
Q

How is didanosine metabolisized?

A
  • The active form is the triphosphate of the adenosine analog
  • Adenosine deaminase catalyzes the interconversion of ddI and ddA
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13
Q

What is the correct form of didanosine?

A

ddA

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14
Q

Structure of Stavudine? MOA?

A

d4T an unsaturated thymidine analog: bind better competitive inhibition becomes primary, chain termination is secondary
MOA: ddT-TP is a competitive inhibitor and a chain terminator

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15
Q

Metabolism of Stavudine?

A

Doesn’t undergo glucuronidation

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16
Q

Structure of lamivudine and emtricitabine? MOA?

A

Lamivudine: 3TC
Emtricitabine: FTC

Structure:
* Hydroxymethyl group is replaced by a sulfer atom (better binding) -> oxathiolanyl nucleosides
* L-nucleosides

MOA: triphosphate are competitive inhibitors -> no mitochandrial toxicity

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17
Q

Benefits of having a drug in L-enantiomer?

A
  1. Mimic natural D-nucleosides and has the ability to act as a hinge
  2. L-nucleosides are often less toxic to cells
  3. More stable against enzymatic degradation
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18
Q

Metabolism of lamivudine and emtricitabine?

A

Glucoronidation

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19
Q

Why was the the development of lamivudine so improtant?

A

AZT (zidovudine) was orginally the only antiretroval drug for years but resistance was extensive and significantly toxic:
* Combination with 3TC allows lower dosage of each drug and double mutants provided suboptimal fitness

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20
Q

Why are combination of 3TC/FTC and AZT or NRTIs products so favorable?

A

Cross resistance between D- and L-nucleosides is unusual

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21
Q

What is the major mechanism responsible for the resistance to lamivudine?

A

M184V/I point mutation (mutation of Met184 to Val or Ile) -> lose sulfur and H-bond potential

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22
Q

Structure of Abacavir?

A

ABC: carbocyclic unsaturated adenosine analog

23
Q

ADR of abacavir?

A

Allergic reaction can be fatal:
* Screening for HLA-B*5701 allele and decrease risk for hypersensitivity rx

24
Q

MOA of Abacavir?

A

Metabolized to the guanosine triphosphate analog (carbovir triphosphate), a competitive inhibitor of RT

25
Metabolism of abacavir?
Eliminated by metabolism to carboxylic acid and glucoronidation
26
Structure of tenofovir disoproxil?
TNF: an acyclic 2'deoxyadenosisne monophosphate analog
27
MOA of tenofovir?
Inhibition and chain termination: 1. Only 2 phosphorylation steps 2. Tenofovir -> MP -> DP 3. Contains a phosphate group that can't be cleaved by esterases making it difficult to cleave off compounds
28
Resistance mechanism of tenofovir disoproxil?
K65R (Lysine to Arginine) mutation
29
What is the active form of tenofovir disoproxil?
Disphosphate
30
How is tenofovir alafenamide activated?
Esterase or spontaneous metabolism
31
What is the rate limiting step of NTRIs?
Phosphorylation of nucleosides to monophosphate -> broad SOA and require differen enzymes
32
What is the MOA of non-nucleoside reverse transcriptase inhibitors?
Bind to allosteric site of RT -> inhibiting it * binding is relatively loose * Doesn't inhibit cell DNA polymerase
33
Resistance of NNRTIs?
Doesn't compete with natural sbstrates -> low barrier to resistance * A single mutation can lead to widespread class resistance * Are not cross-resistant with NRTIs
34
What are the major drawbacks of NNRTIs?
1. Rapid induction of resistance therefore only used in combo therapies 2. Extensively metabolized by CYP450
35
Describe the binding patterns of etravirine?
Lysine 103 (K103N) and tyrosine 181 (Y181C) which are susceptible to mutation that disrupts ring stacking of drug
36
Metabolism of delaviridine?
1. CYP3A4 catalyzed aromatic hydroxylation 2. CYP3A4 o 2D6 catalyzed dealkylation 3. Deleviridine irreversibly inhibits CYP3A4 via suicide mechanism
37
Metabolism of rilpivirine?
Drug retains sufficient activity against K103N and Y181C reverse transcriptase mutants through the oxidation of dimethylphenyl ring
38
What are the genomes that are targeted by PIs?
Gag, pol, env
39
What is the function of HIV protease?
1. Post-translation activation of viral poteins 2. Activation of RT -> PIs are synergistic with NRTIS and NNRTIs
40
What is the function of gag protein?
Determine retroviral core
41
What is the function of pol protein?
Encodes for RT and integrase
42
Function of env protein?
Encodes for envelope protein and determines viral tropism
43
MOA of PIs?
Competitive inhibitors and binds to catalytic site: * **Hydroxyethyamine scaffold** mimic normal peptide linkage/transition state that is cleaved by HIV protease
44
Describe the binding and cleavage of protease?
8 bidning sies are available * HIV protease cleaves between Phe and Pro
45
Describe the design of PI?
1. Mimics the transition state of rx mechanism 2. Must be stable to cleavage (Hydroxyethylamine isostere is effectiv and interacts with catalytic aspartatese) * Tetrahedral intermediate is not a stable anomeric center
45
Describe substrat enzyme binding interaction?
1. Water acts as through coupling (flap region) 2. Asp-Asp acts as catalytic region that cleaves bond within the tetrahedrl intermediate 3. Multiple H-bon interactions with native peptide
46
Describe the binding of phenprocoumon?
Lactone oxygens form H-bonds directly to Ile-50 and Ile-50' in the enzyme flaps * Less likely to develop corss resistance with other PIs
47
DDIs of PIs?
Substrates and inhibitors of CYP3A4: * Ritonavir is a potent CYP3A4 and 2D6 inhibitor -> used as a booster instead of monotherapy
48
Resistance mechanisms against PIs?
1. Peptidomimetic PIs show cross resistance due to structural similarities 2. Tipranavir has less cross resistance because of its chemical structure
49
ADRs of PIs?
Lipodystrophy
50
SAR of INSTIs?
1. Hydrophobic benzyl ring to bind to hydrophobic pocket 2. Chelating triad that can complex 2 Mg2+ cations
51
Due to structure, how is enfuvirtide administered?
Oligopeptide (lipophilic): SC BID
52
MOA of enfuvirtide?
Binds to gp41 -> inhibiting fusion
53
# 2 MOA of maraviroc?
1. CCR5 corector antgonist -> anti-HIV cell entry inhibitor 2. MAcrophages (M-tropic) strains of HIV use the chemokine receptor 5 (CCR5) as a coreceptor 3. T cell (T-tropic) strains use recept CXCR4

Drug Action IV (28 decks)

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