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ID exam 4 > antiviral med chem > Flashcards

antiviral med chem Flashcards

1
Q

Human immunodeficiency virus

A

Enveloped retrovirus
Genus lentivirus
Targets CD4+ T cells, macrophages, and dendritic cells
Directly and indirectly destroys CD4+ T cells
Causes immunosuppression
Pathology associated with opportunistic infections and cancer
HIV-1 is more virulent and more easily transmitted
-Responsible for most infections
HIV-2 - primarily found in West Africa

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2
Q

key steps in HIV life cycle

A

initial binding
uncoating of the viral RNA
reverse transcription (viral RNA - proviral DNA)
integration of proviral DNA into the host genome
transcription of proviral DNA to form mRNA
translation of viral mRNA to form viral polyprotein
cleavage of the viral polyprotein to form the mature proteins of the virus
assembly and budding

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3
Q

NRTIs

A 
Abacavir - ABC
Didanosine - DDI
Emtricitabine - FTC
Lamivudine - 3TC
Stavudine - D4T
Tenofovir (2 forms) - TDF&TAF
Zidovudine - ZDV/AZT
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4
Q

NNRTIs

A 
Delavirdine - DLV
Efavirenz - EFV
Etravirine - ETR
Nevirapine - NVP
Rilpivirine - RPV
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5
Q

Integrase inhibitors (INI)

A

Dolutegravir - DTG
Elvitegravir - EVG
Raltegravir - RAL

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6
Q

protease inhibitors

A 
Atazanavir - ATV
Darunavir - DRV
Fosamprenavir - FPV
Indinavir - IDV
Lopinavir - LPV
Nelfinavir - NFV
Saquinavir - SQV
Tipranavir - TPV
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7
Q

entry and fusion inhibitors

A

Enfuvirtide - ENF/T-20

Maraviroc - MVC

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8
Q

pharmacokinetic boosters

A

Ritonavir - RTV

Cobicistat - COBI

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9
Q

HIV fusion/entry

A

HIV gp120 binds to CD4 on target cell
Conformational changes in gp120 exposes region
Exposed region binds to cytokine receptor (CCR5 or CXCR4 depending on the strain of HIV)
Normal chemokine receptor ligands can interfere with HIV binding and fusion

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10
Q

Maraviroc

A

HIV entry inhibitor
Selective CCR5 antagonist
Binds to CCR5 and causes a conformation change that prevents gp120 binding
No effect on cell surface levels of CCR5 or on CCR5 signaling
Can only be used in patients with HIV strains that utilize CCR5*
Can only be used in patients with HIV strains that utilize CCR5*
Potential problem:
-May select for viral mutants that bind to CXCR4
-Almost all transmitted HIV isolates bind CCR5
-Rest either bind to CXCR4 only or to both co-receptors
-In ~60 % of patients, strains that bind CXCR4 emerge late during infection - Emergence is correlated with rapid disease progression

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11
Q

Enfuviritide

A

fusion inhibitor
36 amino acid peptide that inhibits fusion of virus membrane with cell membrane
Active only against HIV-1
Must be injected subcutaneously
resistance:
-Acquired resistance is due to mutations within a 10 amino acid motif in gp41 - Forms part of the binding site of enfuvirtide, critical for viral fusion
-Easily acquired

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12
Q

HIV RT

A

synthesizes 1st and 2nd strand DNA

NRTIs interfere with 1st and 2nd strand DNA synthesis

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13
Q

NRTI mechanism

A

NRTIs are nucleoside analogs that lack the 3’ OH
-Sometimes called false nucleotides
Two effects:
-Competitive inhibitor of reverse transcriptase
-DNA chain terminator - inhibit elongation
Active against HIV-1 and HIV-2

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14
Q

NRTIs

A

7 NRTIs currently available for clinical use
Form backbone of initial therapy
Used in combination: 2 NRTIs plus NNRTI or PI or integrase inhibitor
Some combinations of NRTIs work better than others
-Tenofovir and emtracitabine
-Abacavir and lamivudine
All must be activated by cellular kinases to triphosphate form (or equivalent)
Each NRTI is phosphorylated to triphosphate
Use cellular enzymes
Compete with normal nucleosides and NRTIs that are analogs of the same nucleoside

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15
Q

TDF

A

Prodrug - converted to tenofovir (TFV)
Acyclic nucleoside phosphonate analog of adenosine
Requires 2 phosphorylation steps
Phosphonate cannot be cleaved by cellular esterases - catabolically stable
advantages: Long intracellular half life, Different resistance profile – different mutations in RT confer resistance, Retains some activity against mutant RT, Highly selective for HIV RT over human cellular and mitochondrial DNA polymerases
problems: Plasma esterases can activate TDF to TFV, TFV is eliminated by kidney, Relative to other NRTIs, TDF treatment is associated with: greater loss of kidney function and a higher risk of acute renal failure, larger reduction in bone mineral density

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16
Q

TAF

A 
Alternative tenofovir prodrug
Activated by different pathway than TDF
-Lower plasma concentrations of TFV
-Increased accumulation in lymphocytes
-Expected to have fewer side effects
May be even better at targeting HIV
-Better accumulation in lymph nodes
-Higher intracellular concentrations
TAF contains phenol and alanine isopropyl ester to mask the charge on the phosphonate
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17
Q

NRTI activation

A

Nucleosides and NRTIs must be activated to their triphosphate forms by cellular kinases
Different kinases are responsible for adding the first, second and third phosphate to the same nucleoside
Different nucleosides require different kinases to activate them
A given nucleoside and its corresponding NRTI are activated by the same enzymes
NRTI analogues of the same nucleoside can compete with each other for activation
Activated NRTIs compete with dATP, dCTP, dGTP, and dTTP to be incorporated into the growing DNA chain by RT
Ratio of activated NRTI to dNTPs is important
NRTIs have a higher affinity for HIV RT than for cellular DNA polymerases
Some NRTIs inhibit mitochondrial DNA polymerase
TDF and TAF must be processed to TFV by cellular enzymes before phosphorylation
Tenofovir requires 2 phosphorylation steps

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18
Q

anti-HIV drug resistance

A

Why do resistant mutations arise so quickly?
-HIV polymerase is error prone
-RT inhibitors are unable to suppress viral replication > 90%
-Large amounts of virus present - 10^7 to 10^8 infected cells, Half-life of infected cells is 1 - 2 days, HIV-1 genome is 9,181 nt, HIV RT has an error rate of ~1/2000
Rate at which mutations appear is inversely related to the serum drug concentration - Need to maintain drug levels above MIC

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19
Q

genetic barriers to antiviral drug resistance

A

Genetic barrier = ease with which drug resistance develops
-Low = easy for virus to become resistant
-High = hard for virus to become resistant
-Evolution of a viral population that overcomes the activity of a drug or drug regimen
-Depends on: Number of mutations required, Impact of each mutation on drug activity, Impact of each mutation of virus replication (fitness), Number of pre-existing mutations in the viral population
Low genetic barrier – resistance develops easily - single mutation with low cost to viral fitness
High genetic barrier – more difficult to develop resistance
Two common scenarios:
-A primary mutation that has a high fitness cost – i.e., makes the virus less able to replicate - one or more additional mutations needed to allow the virus to grow better
-Multiple mutations needed for complete resistance
Drugs with low genetic barriers can be used in combination to develop an effective therapy

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20
Q

NRTI resistance

A

Discriminatory mutations - Mutations that selectively impair the ability of reverse transcriptase to incorporate analogues into DNA
Excision mutations - ATP molecule mediates the removal (excision) of a nucleoside analogue after it has been incorporated; selected by thymidine analogs AZT and d4T
Mutations are mainly near the RT active site, but can occur at more distant locations
Mutations can either help the RT to distinguish between normal dNTPs and NRTIs or can promote removal of NRTIs after they’ve been incorporated into the growing chain
Individual NRTIs have a low genetic barrier
Some mutations confer resistance to a subset of NRTIs, but make RT more susceptible to inhibition by others
-NRTIs in preferred combination for initial therapy take advantage of this phenomenon

21
Q

AEs of NRTIs

A

Mitochondrial toxicity
-NRTIs are selective for HIV RT over human DNA polymerase-a and –b
-Some NRTIs inhibit human DNA polymerase-g
-Leads to anemia, granulocytopenia, myopathy, peripheral neuropathy, and pancreatitis
-Lactic acidosis and hepatic steatosis (buildup of fat droplets in liver cells) - More common with d4T, ZDV & ddI
Lipoatrophy – loss of body fat - Higher incidence with stavudine

22
Q

Abacavir hypersensitivity reaction

A

Abacavir Hypersenstivity Reaction : Black Box Warning
Ocurs in 4 - 8 % of patients - can be fatal
Symptoms - Malaise, Dizziness, Headache, GI disturbances
Discontinue immediately is symptoms develop - Prompt recovery
Highly associated with the HLA-B5701 allele
Testing for HLAB5701
is recommended before initiating treatment with abacavir

23
Q

NRTI recommended combinations

A

Tenofovir and emtracitabine**
-TFV has long intracellular half-life
-Once daily dosing
-Equivalent efficacy to other NRTI combinations
-Less fat maldistribution
-Different resistant mutation profiles
Abacavir and lamivudine (or emtracitabine) - If HLA-B*5701 negative
** Lamivudine and emtricitabine are interchangeable - Have negligible side effects; select for the M184V mutation that can confer improved susceptibility to zidovudine or tenofovir

24
Q

antiretroviral medications that should not be recommended at any time

A

Monotherapy (except possibly zidovudine used to prevent perinatal HIV transmission)
Dual NRTI therapy (with no other antiretroviral)
3-NRTI regimen (except abacavir/lamivudine/ zidovudine and possibly lamivudine/zidovudine + tenofovir)

25
Q

NNRTIs

A

Bind directly to site on RT
-Hydrophobic pocket near catalytic site
-Near, but distinct from that of NRTIs
-Binding affects flexibility of enzyme
-NNRTIs do NOT compete with nucleotides for binding - noncompetitive inhibitors
NNRTIs do not have to be phosphorylated
Block RNA- and DNA-dependent DNA polymerase activities

26
Q

NNRTI MOA

A

In the presence of NNRTI, nucleoside triphosphate and
template bind tightly to RT, but nonproductively
Blocks polymerization
Single mutation in binding site can promote resistance

27
Q

NNRTIs AEs

A

All NNRTIs: Rash, Drug-drug interactions
Nevirapine – hepatotoxicity (may be severe and life threatening), rash including Stevens-Johnson syndrome
Efavirenz - neuropsychiatric, teratogenic in nonhuman primates (FDA Pregnancy Category D)

28
Q

NNRTI metabolism

A

All are metabolized by CYP3A
-Efavirenz, nevirapine, and etravirine are moderate inducers
-Efavirenz and delavirdine are inhibitors of CYP3A4
-Etravirine inhibits CYP2C9 and CYP2C19
Potential for interactions with other drugs that are metabolized by CYP3A
-CYP3A4 inducers (rifampin) can reduce levels
-CYP3A4 inhibitors can increase levels

29
Q

NNRTI summary

A

NNRTIs do not require activation, do not compete with dNTPs, and are not incorporated into DNA
NNRTIs do not bind to cellular DNA polymerases
Resistance to NNRTIs can be acquired through a single mutation
Mutations that confer resistance to NNRTIs do not cause resistance to NRTIs

30
Q

integrase inhibitors

A

Raltegravir (Mk-0518) approved in 2007
Inhibits insertion of HIV DNA into the human genome
Most commonly reported treatment-related adverse effects were diarrhea, nausea, fatigue, headache, and itching
Orally available
Compatible with other antiretroviral drugs
Does not interact with CYP450s**

31
Q

Integrase function

A

Inserts HIV DNA into host cell DNA
2 steps: 3’-processing, Strand transfer
Raltegravir inhibits the strand transfer step

32
Q

Raltegravir mechanism

A

Integrase inhibitors
Integrase uses divalent metal ions to catalyze insertion - Coordinated by 3 amino acids in active site
Raltegravir chelates both metal ions and stabilizes enzyme-DNA complex

33
Q

INI resistance

A

Caused by primary mutations that reduce INI susceptibility
-secondary mutations further decrease virus susceptibility and/or compensate for the decreased fitness
Low genetic barrier - Dolutegravir higher
extensive but incomplete cross resistance - Dolutegravir less affected

34
Q

Elvitegravir

A

Integrase inhibitor
currently available only in coformulation with cobicistat (COBI), FTC, and TDF or TAF
cobicistat is not active against HIV
Role is to boost elvitegravir concentrations by inhibiting metabolism by CYP3A4

35
Q

Dolutegravir

A 
Integrase inhibitor
Long plasma half life (14h) - once daily dosing
No boosting
No interactions with CYP3A4
Higher barrier for resistance
36
Q

HIV protease inhibitors

A

HIV protease is an aspartic protease - aspartic acid in active site
Dimer - active site formed at interface
Inhibitors are transition state mimetics - Peptidomimetic, Nonpeptide compounds

37
Q

HIV protease mechanism

A

Peptide bond cleavage is a hydrolysis reaction
Protease catalyzes addition of water to the amide
Forms intermediate
Breaks down to the two products, a carboxylic acid and an amine

38
Q

HIV protease inhibitors

A

Amide bond is replaced by non-cleavable linkages
All PIs except tipranavir are considered peptidomimetics
Inhibitor binding causes a conformation change in protease - “flaps” close

39
Q

metabolism of protease inhibitors

A

All are substrates and some are inhibitors of CYP3A4
High potential for drug interactions
Can cause increases in levels of other CYP3A4 metabolized drugs
Levels of PI can be influenced by other CYP3A4 inhibitors
Interactions are complicated
-Delavirdine increases indinavir and saquinavir levels
-Efavirenz reduces indinavir and saquinavir levels

40
Q

saquanivir

A

First protease inhibitor approved by FDA
Contains hydroxyethylamine moiety in place of peptide bond
Low bioavailability as hard gel capsule (4%)
Soft gel capsule increases bioavailability 3-fold

41
Q

ritonavir

A

Higher bioavailability - 75% - Increased with food
Most potent PI inhibitor of CYP450s**
Sub-therapeutic doses of ritonavir can be combined with other PIs - PI boosting
Currently recommended initial treatment regimes all use ritonavir combinations

42
Q

PI boosting

A 
Low doses of ritonavir inhibit CYP3A4
-Block metabolism of other PIs
-Increases serum concentrations - Lopinavir and tipranvir are not indicated for use except in combination with ritonavir
-Increases trough levels
-Reduces emergence of resistant viruses
-Improves compliance - reduced dosing, fewer pills, eliminates food restrictions
Disadvantages:
-Drug-drug interactions with ritonavir
-Increased risk of hyperlipidemia
43
Q

Atazanavir

A

Once-daily dosing and minimal lipid and glycemic effects
most potent protease inhibitor in vitro prior to darunavir
Different resistant mutation profile
Efavirenz and tenofovir reduce ATV concentrations

44
Q

Darunavir

A

Novel peptidomimetic PI
Preferred PI for initial antiretroviral combinations
Two unique features:
-Makes extensive hydrogen bonds with protease backbone
-Inhibits HIV protease dimerization

45
Q

Tipranavir

A

Novel nonpeptidic PI
Retains activity against proteases in highly treated patients
Selects for different set of resistance mutations
CYP3A4 substrate and inducer

46
Q

protease inhibitor resistance

A

Highest genetic barrier of antiretrovirals
Mutations can be in active site or far away
Modify contacts between protease and inhibitor - Reduce affinity of protease for inhibitor
Protease inhibitors bind tightly to protease
Natural substrates have variable, less tight binding
Resistance mutations have greater effect on PI than natural substrate
Most mutations occur in or near substrate cleft of protease
Some occur at distant sites and act indirectly
Multiple mutations are usually needed to confer high level resistance
DRV retains activity against most PI-resistant mutant proteases ***
Some mutations confer resistance to some PIs, but increase the susceptibility to others - Example: I50L, Confers resistance to atazanavir, Increased susceptibility to other PIs

47
Q

PI AEs

A

Hyperlipidemia
Insulin resistance and diabetes
Lipodystrophy (changes in body fat accumulation)
Elevated liver function tests
Possible increased bleeding risk in hemophiliacs
Drug-drug interactions

48
Q

initial HAART - INSTI based

A

DTG/ABC/3TC; only if HLA-B*5701 negative
DTG (QD) + TDF/FTC
EVG/COBI/TDF/FTC; only if pre-ART CrCl over 70 mL/min
EVG/COBI/TAF/FTC; only if pre-ART CrCl ≥30 mL/min
RAL + TDF/FTC

49
Q

initial HAART - PI based

A

DRV/r (QD) + TDF/FTC

ID exam 4 (9 decks)

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