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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
Q

Metabolism of abacavir?

A

Eliminated by metabolism to carboxylic acid and glucoronidation

26
Q

Structure of tenofovir disoproxil?

A

TNF: an acyclic 2’deoxyadenosisne monophosphate analog

27
Q

MOA of tenofovir?

A

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
Q

Resistance mechanism of tenofovir disoproxil?

A

K65R (Lysine to Arginine) mutation

29
Q

What is the active form of tenofovir disoproxil?

A

Disphosphate

30
Q

How is tenofovir alafenamide activated?

A

Esterase or spontaneous metabolism

31
Q

What is the rate limiting step of NTRIs?

A

Phosphorylation of nucleosides to monophosphate -> broad SOA and require differen enzymes

32
Q

What is the MOA of non-nucleoside reverse transcriptase inhibitors?

A

Bind to allosteric site of RT -> inhibiting it
* binding is relatively loose
* Doesn’t inhibit cell DNA polymerase

33
Q

Resistance of NNRTIs?

A

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
Q

What are the major drawbacks of NNRTIs?

A
  1. Rapid induction of resistance therefore only used in combo therapies
  2. Extensively metabolized by CYP450
35
Q

Describe the binding patterns of etravirine?

A

Lysine 103 (K103N) and tyrosine 181 (Y181C) which are susceptible to mutation that disrupts ring stacking of drug

36
Q

Metabolism of delaviridine?

A
  1. CYP3A4 catalyzed aromatic hydroxylation
  2. CYP3A4 o 2D6 catalyzed dealkylation
  3. Deleviridine irreversibly inhibits CYP3A4 via suicide mechanism
37
Q

Metabolism of rilpivirine?

A

Drug retains sufficient activity against K103N and Y181C reverse transcriptase mutants through the oxidation of dimethylphenyl ring

38
Q

What are the genomes that are targeted by PIs?

A

Gag, pol, env

39
Q

What is the function of HIV protease?

A
  1. Post-translation activation of viral poteins
  2. Activation of RT -> PIs are synergistic with NRTIS and NNRTIs
40
Q

What is the function of gag protein?

A

Determine retroviral core

41
Q

What is the function of pol protein?

A

Encodes for RT and integrase

42
Q

Function of env protein?

A

Encodes for envelope protein and determines viral tropism

43
Q

MOA of PIs?

A

Competitive inhibitors and binds to catalytic site:
* Hydroxyethyamine scaffold mimic normal peptide linkage/transition state that is cleaved by HIV protease

44
Q

Describe the binding and cleavage of protease?

A

8 bidning sies are available
* HIV protease cleaves between Phe and Pro

45
Q

Describe the design of PI?

A
  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
Q

Describe substrat enzyme binding interaction?

A
  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
Q

Describe the binding of phenprocoumon?

A

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
Q

DDIs of PIs?

A

Substrates and inhibitors of CYP3A4:
* Ritonavir is a potent CYP3A4 and 2D6 inhibitor -> used as a booster instead of monotherapy

48
Q

Resistance mechanisms against PIs?

A
  1. Peptidomimetic PIs show cross resistance due to structural similarities
  2. Tipranavir has less cross resistance because of its chemical structure
49
Q

ADRs of PIs?

A

Lipodystrophy

50
Q

SAR of INSTIs?

A
  1. Hydrophobic benzyl ring to bind to hydrophobic pocket
  2. Chelating triad that can complex 2 Mg2+ cations
51
Q

Due to structure, how is enfuvirtide administered?

A

Oligopeptide (lipophilic): SC BID

52
Q

MOA of enfuvirtide?

A

Binds to gp41 -> inhibiting fusion

53
Q

2

MOA of maraviroc?

A
  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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