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Microbiology E-Books > Anti-HIV Drugs I > Flashcards

Anti-HIV Drugs I Flashcards

1
Q

CD4+ count / HIV-1 RNA levels have been used for decades to measure

A

HIV progression

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2
Q

Measure the state of the patients immune system and susceptibility to opportunistic infections

A

CD4+

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3
Q

Particularly effective at monitoring therapeutic intervention

A

HIV-1 RNA levels

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4
Q

RNA levels drop 10-100 fold within week of treatment with

A

Protease or RT inhibitor

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5
Q

99% of plasma HIV arises from recently infected

A

CD4 lymphocytes

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6
Q

For viral entry, CD4 receptor or CCR5 coreceptoron CD4+ cells strip

A

gp120 from viral surface

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7
Q

Then, naked gp41 transmembrane protein uncoils and sticks end into nearby

A

CD4 cells

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8
Q

The uncoiled protein reassociatesN and C terminal regions, thus reeling in

A

CD4

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9
Q

Peptide binds specifically in the groove of a coiled coil in the gp41 protein

-Binds the N36 helix

A

Enfuvirtide

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10
Q

Synthetic 36 amino acid that works on HIV-1 but not HIV-2

-Provides significant benefit when added to cocktail of other drugs

A

Enfuvirtide

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11
Q

High first pass metabolism. Requires subcutaneous injection twice a day

A

Enfuvirtide

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12
Q

What are the side effects of Enfuvirtide?

A

Skin reaction at site of infection and greater incidence of penumonia

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13
Q

Resistance to enfuvirtide correlates with the appearance of mutations in the N-terminal portion of

A

gp41

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14
Q

Blocks HIV entry by binding the human CCR5 coreceptor

A

Maraviroc

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15
Q

Discovered because individuals with certain CCR5 mutations were highly HIV resistant

A

Maraviroc

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16
Q

Maraviroc only works for HIV isolates that utilize

A

CCR5

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17
Q

Maraviroc does not work for those that use

A

CXCR4

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18
Q

Drug is metabolized by P450s so inducers and inhibitors of system may influence levels

A

Maraviroc

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19
Q

1% of patients using maraviroc can experience

A

MI’s

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20
Q

Resistance to miraviroc is due to the emergence of mutant strains that use

A

CXCR4 to gain entry

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21
Q

FDA approved (2018), monoclonal antibody therapy for multi-drug resistant HIV who fail other treatment protocols

A

Ibalizumab

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22
Q

Binds CD4 receptor and blocks viral entry. Works for CCR5 and CXCR4 tropic HIV isolates

A

Ibalizumab

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23
Q

Ibalizumab does not interfere with normal

A

CD4 activity

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24
Q

Taken by IV infusion every 14 days

-Adverse effects include, diarrhea, dizziness and rash

A

Ibalizumab

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25
Q

RT and all other polymerases that create DNA strands must work off a free

A

3’ Hydroxyl end

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26
Q

In this case, serves as a 3’ hydroxyl primer

A

tRNA

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27
Q

In reverse transcription, RNA is degraded as the first DNA strand is

A

Synthesized

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28
Q

The final bit of RNA is left to serve as a primer for the

A

Second DNA strand synthesis

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29
Q

During reverse transcription, double stranded HIV DNA genome is integrated into host

A

Genome

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30
Q

RT polypeptide contains both the

A

RT and RNAse activities

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31
Q

The RT crystal structure resembles a

A

Hand

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32
Q

Located at the fingers area

A

RT

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33
Q

The RNAseH active site is located at the junction of the

A

“Wrist”

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34
Q

The nucleoside reverse transcriptase inhibitors are essentially just

A

Nucleoside analogues without a free 3’ OH

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35
Q

In DNA synthesis, 3’-OH of growing DNA chain is catalyzed to attack the alpha phosphate of a

A

dNTP

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36
Q

When a chain terminator is incorporated, there is no

A

3’ OH to continue rection

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37
Q

Act as suicide substrates by poisoning RT chain elongation

-Drugs bind the active site of the HIV RT

A

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

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38
Q

Selectivity because drugs do not bind well to nuclear DNA polymerases

A

NRTIs

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39
Q

Prodrugs that must be triphosphorylated by cytoplasmic enzymes

-Taken orally and generally well absorbed from GI

A

NRTIs

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40
Q

The half-life of NRTIs is usually extended by transport into the cell and subsequent

A

Phosphorylation

41
Q

NRTIs can poison host DNA polymerases, particularly mitochondrial polymerases, which leads to potentially fatal

A

Lactic Acidosis

42
Q

Resistance to NRTIs is due to mutations in the

A

RT active site

43
Q

Develops more rapidly than other NRTIs

A

Lamivudine resistance

44
Q

NRTIs are prodrugs because they lack some or all phosphates necessary for

A

DNA synthesis

45
Q

This is necessary though because if drugs were triphosphates, their excessive charge would prevent transport into the

46
Q

Instead, prodrugs enter cell, and are then converted to triphosphates by

A

Host enzymes

47
Q

Traps the NRTIs inside the cell, thereby adding to efficacy

A

Phosphorylation

48
Q

Fluorinated analog of lamivudine with long t1/2

A

Emtricitabine

49
Q

Clinically significant drug-drug (p450) interactions have not been identified with

A

Emtricitabine

50
Q

Synthetic adenosine analog with a phosphate. Technically a nucleotideRT inhibitor

51
Q

Presence of first phosphate overcomes rate limiting phosphorylation step

52
Q

Drug acts by competing with dATP for binding HIV RT and then chain terminates

53
Q

Long term use of tenofovir can cause nephrotoxicity and a decrease in

A

Bone mineral density

54
Q

The newest version of tenofovir which shows less bone and kidney toxicity than the previous tenofovir disoproxil, but higher lipid levels

A

Tenofovir alafenamide

55
Q

Emtricitabine and tenofovir alafenamide are coformulated as

56
Q

Bind adjacent to the RT active site, inducing a conformational change that blocks RT activity

57
Q

Non-NRTIs do not require

A

Cellular activation

58
Q

Non-NRTIs act on

A

HIV-1 but not HIV-2

59
Q

Resistance to non-NRTIs develops

60
Q

NNRTIs interact with P450 CYP3A4 and either inhibit or induce

A

P450 activity

61
Q

Some non-NRTI patients can undergo methadone withdrawal on nevirapinedue to

A

CYP3A induction

62
Q

Increases levels of co-administered PIs

A

Delavirdine

63
Q

Can lead to a false positive cannabinoid test, and central nervous system and psychiatric problems

64
Q

Selected on the basis of activity toward HIV-resistant to more common NNRTIs

-Next generation NNRTI

A

Etravirine

65
Q

Persistent activity of etravirine despite mutations in active site is based on concept of

A

Strategic flexibility

66
Q

The drug will likely be reserved for patients who have failed traditional treatment protocols and developed resistance to NNRTIs

A

Etravirine

67
Q

Stalled integrating DNA is degraded or converted to non-replicating

A

DNA circles

68
Q

By cleaving termini of virus, the integrase creates active 3’-hydroxyl ends that are poised to integrate into DNA of the

A

Human genome

69
Q

Only bind the Integrase/Viral DNA complex

A

Integration inhibitors

70
Q

Binds Mg2+ and displaces the terminal nucleotide from the active site

A

HIV integrase inhibitor (MK2048

71
Q

The first HIV integrase strand transfer inhibitor (INSTI)

A

Raltegravir

72
Q

Inhibits strand-transfer actions mediated by HIV viral integrase

A

Raltegravir

73
Q

Binds Mg2+in the active site of Integrase-DNA complex

A

Raltegravir

74
Q

Raltegravir does not interact with the

A

P450 system

75
Q

Raltegravir is metabolized by

A

Glucuronidation

76
Q

A first-line therapy

-Extremely potent

A

Raltegravir

77
Q

FDA approved in 2012 for use in once-a-day combo pill (Stribild)

-Similar mechanism and resistance profile as raltegravir

A

Elvitegravir

78
Q

Boosts elvitegravir half-life by inhibiting CYP3A4 metabolism

-Has no anti-viral activity of its own

A

Cobicistat

79
Q

Remains active in patients who have become resistant to earlier integrase inhibitors

-Does not require boosting by cobicistat

A

Dolutegravir

80
Q

Co-formulated as Triumeq with abacavir and lamivudine. Once daily dosing

A

Dolutegravir

81
Q

Avoid in HLA-B*5701 positive patients because of potential abacavir sensitivity

A

Dolutegravir

82
Q

FDA approved in March 2018 for use in once-a-day combo pill (Biktarvy), which also contains tenofovir alafenamide and emtricitabine

A

Bictegravir

83
Q

Bictegravir does not require boosting by

A

Cobicistat

84
Q

Recommended for treatment-naive patients, as well as an alternative for patients who are effectively treated by other regimes (>50 HIV RNA c/mL)

A

Bictegravir

85
Q

Bictegravir is a substrate for

86
Q

Before using bictegravir, we want to test patients for co-infection with

87
Q

Cleaves the chimeric gag-pol protein into a set of active enzymes (reverse transcriptase, protease, integrase) and into a set of structural proteins (p17, p24, p9, and p7)

A

HIV proteases

88
Q

Recognition by proteases is based on

A

Shape (not volume)

89
Q

Each subunit of the protease dimer contributes an aspartic acid to form the

A

Catalytic site

90
Q

Human aspartic acid proteases function as monomers and thus evade

A

Viral protease inhibitors

91
Q

Each is an analog of the transition state. A tertiary alcohol often with a recognizable phenylalanine

A

Protease inhibitor

92
Q

All viral protease inhibitors bind the active site

A

Reversibly

93
Q

These residues activate a water molecule that attacks HIV peptide between Phe(or Tyr) and Pro

A

Protease active site aspartate residues

94
Q

Lower plasma RNA levels 100-1000 fold within 4-12 weeks of therapy

A

Protease inhibitors

95
Q

When combined with two nucleoside analogs, 60-95% of first-time patients achieve viral levels below detection limit

A

Protease inhibitors

96
Q

Generally occurs in a stepwise manner

A

Resistance to protease inhibitors

97
Q

Changes in body fat distribution, i.e. lipodystrophy syndrome or pseudo-Cushing’s syndrome are examples of the adverse effects of

A

Protease inhibitors

98
Q

Protease inhibitors can also cause

A

Hyperlipidemia

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