Antivirals 2 Flashcards
HIV - Reverse transcriptase inhibitors
Reverse transcriptase (RT) has three activities
1) RNA dependent DNA polymerase
2) ___ H
3) DNA dependent DNA polymerase
RT does the following
- Copies plus-strand RNA to produce minus-strand ___
- Degrades RNA template from RNA-DNA hybrid
- Synthesizes ___ -strand ___ from minus-strand DNA template
- Ribonuclease
- DNA
- plus, DNA
Nucleoside RT inhibitors (NRTIs) mechanism
NRTIs are nucleoside analogs that lack the ___
- Sometimes called false nucleotides
Two effects
- ___ inhibitor of reverse transcriptase
- DNA chain ___ - inhibit elongation
- 3’ OH
- competitive
- terminator
Nucleoside RT inhibitors (NRTIs)
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 ___
- ___ and lamivudine
all must be activated by celluar kinases to ___ form
- emtricitabine
- Abacavir
- triphosphate
analogs
abacavir: __
tenofovir: __
lamivudine: __
emtricitabine: __
G
A
C
C
NRTIs must be phosphorylated
- Each NRTI is phosphorylated to triphosphate.
- Use ___ enzymes.
- ___ with normal nucleosides and NRTIs that are analogs of the same nucleoside
cellular
Compete
Tenofovir alafenamide (TAF)
Activated by different pathway than previous tenofovir
- Lower plasma concentrations of tenofovir (good so no kidney damage)
- Increased accumulation in ___
- However, TAF is associated with higher ___ levels compared to tenofovir disoproxil fumarate
May be even better at targeting HIV
TAF is converted to ___
Different activation pathway of TAF allows for 10-fold ___ dose compared to TDF
- lymphocytes
- lipid
- TFV
- lower
Activation of NRTIs - summary
Activated NRTIs ___ with dATP, dCTP, dGTP, and dTTP to be incorporated into the growing DNA chain by RT (ratio important)
- NRTIs have a higher affinity for HIV ___ than for cellular DNA ___
- TAF must be processed to TFV by ___ enzymes before phosphorylation
- requires 2 phosphorylation steps
compete
- RT, polymerases
- cellular
Resistance to anti-HIV drugs
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
Rate at which mutations appear is ___ related to the serum drug concentration
- Need to maintain drug levels above MIC
Resistance
- ___ mutations - bouncer
- ___ mutations - plucked out
- inversely
- Discriminatory
- Excision
Resistance to NRTIs - Key points
- Mutations are mainly near the RT ___ site, but can occur at more distant locations
Mutations can either
- help the RT to distinguish between normal dNTPs and NRTIs - bouncer
- promote removal of NRTIs after they’ve been incorporated into the growing chain - plucked out
Individual NRTIs have a ___ genetic barrier of resistance
- active
- low
Some mutations confer resistance to a subset of NRTIs, but make RT more ___ to inhibition by others.
- NRTIs in preferred ___ for initial therapy to take advantage of this phenomenon.
- susceptible
- combination
Adverse effects of NRTIs
___ toxicity
- Leads to anemia, granulocytopenia, myopathy, peripheral neuropathy, and pancreatitis
- Lactic acidosis and hepatic steatosis
___ – loss of body fat
___ Hypersenstivity Reaction: Black Box Warning.
- Highly associated with the ___ allele
- Mitochondrial
- lipoatrophy
- Abacavir, HLA-B*5701
Nonnucleoside RT inhibitors (NNRTIs)
Bind directly to site on RT
- Hydrophobic pocket ___ catalytic site
- Near, but distinct from that of NRTIs
- Binding affects ___ of enzyme
- NNRTIs do NOT compete with nucleotides for binding - ___ inhibitors
- NNRTIs do not have to be ___
- Block RNA- and DNA-dependent DNA ___ activities
- near
- flexibility
- non-competetive
- phosphorylated
- polymerase
NNRTI mechanism of action
- In the presence of NNRTI, nucleoside
triphosphate and template bind tightly to RT, but nonproductively. - Blocks ___
- ___ mutation in binding site can promote resistance
- polymerization
- single
First generation NNRTIs
1) ___
2) efavirenz
3) delavirdine
2nd gen - Designed to be inherently ___
- can bind in multiple orientation
- binds to mutant that are resistant to othe NNRTIs
1) Etravirine
2) ___
- Nevirapine
- flexible
- Rilpivirine
Adverse Effects: NNRTIs
All NNRTIs:
- rash
- drug-drug interaction
___ – hepatotoxicity (may be severe and life- threatening), rash including Stevens-Johnson syndrome
___ - neuropsychiatric, teratogenic in nonhuman primates (FDA Pregnancy Category D)
- nevirapine
- Efavirenz
Metabolism of NNRTIs
All are metabolized by ___
Potential for interactions with other drugs that are metabolized by CYP3A
- inducers ( ___ ) can reduce levels
- inhibitors can increase levels
CYP3A
rifampin
Summary of NNRTIs
- NNRTIs do NOT require activation, do NOT ___ with dNTPs, and are NOT incorporated into DNA
- NNRTIs do NOT bind to cellular DNA polymerases
- Resistance to NNRTIs can be acquired through a ___ mutation
- compete
- single
T or F: Mutations that confer resistance to NNRTIs cause resistance to NRTIs.
FALSE
Integrase inhibitors (INI)
Inhibits ___ of HIV DNA into the human genome
- ___ available
- Compatible with other antiretroviral drugs
- Some do not interact with ___
insertion
- orally
- CYPs
Integrase function
Inserts HIV DNA into host cell DNA
steps:
1) 3’-processing
2) strand transfer
Integrase inhibitors block the ___ step
integrase uses divalent ___ ions to catalyze insertion
- Chelates both metal ions and stabilizes
enzyme-DNA complex
Drugs mimic: ___ acid
4 drugs (-gravir)
strand transfer
metal
Diketo
Raltegravir, Elvitegravir, Dolutegravir, Bictegravir
Integrase inhibitor resistance
Caused by primary mutations that reduce ___ susceptibility
Secondary mutations further decrease virus susceptibility and/or compensate for the decreased fitness
- INI
Integrase inhibitor resistance
Elvitegravir
- Metabolized by CYP3A4
- Currently available only in coformulation with ___ (COBI) - Role is to boost elvitegravir concentrations by inhibiting metabolism by CYP3A4
Dolutegravir
- ___ plasma half life (14h) - once daily dosing
- No boosting required
- No interactions with CYP3A4
- Higher barrier for resistance
Bictegravir
- Low risk of resistance
- Few drug interactions
- Can be started without___ testing
- Cannot be used with rifampin
- Raises ___ levels (~0.1 mg/dL) through inhibition of tubular secretion of creatinine
- Cobicistat
- long
- HLA-B*5701
- SCr
Cobicistat
Designed to inhibit ___
- peptidomimetic
CYP3A4
HIV protease inhibitors
HIV protease is an aspartic protease - aspartic acid in active site
___ - active site formed at interface
Inhibitors are ___ state mimetics
- Peptidomimetic
- Nonpeptide compounds
- dimer
- transition
HIV protease mechanism
Peptide bond cleavage is a ___ reaction
Protease catalyzes addition of water to the amide, forms intermediate
Breaks down to the two products, a carboxylic acid and an amine
hydrolysis
HIV protease inhibitors (PIs)
Amide bond is replaced by non-cleavable linkages
All PIs except ___ are considered
peptidomimetics
Inhibitor binding causes a conformation
change in protease - “flaps” ___
Metabolism
All are substrates and some are inhibitors of ___
- High potential for drug interactions
- Low doses of ___ inhibit CYP3A4 (increase PI serum [ ])
- reduces resistance and improves compliance
Disadvantages
- Drug-drug interactions with ritonavir
- Increased risk of ___
tipranavir
close
CYP3A4
ritonavir
hyperlipidemia
PI - Atazanavir (ATV)
Once-daily dosing and minimal lipid and glycemic effect
- Most potent protease inhibitor in vitro prior to darunavir
- Different resistant mutation profile
- Efavirenz and tenofovir ___ ATV concentrations
reduce
PI - Darunavir (DRV)
Novel peptidomimetic PI
- Preferred PI for initial antiretroviral combinations
- DRV can inhibit both wildtype and mutants that are resistant to other PIs
Two unique features
1) Makes extensive ___ bonds with protease backbone
2) Inhibits HIV protease ___
DRV retains activity against most PI-resistant mutant proteases
- H
- dimerization
Tipranavir (TPV) - PI
- Novel ___ PI
- Retains activity against proteases in highly treated patients, including those resistant to DRV
- Selects for different set of resistance mutations
- ___ substrate and inducer
- nonpeptidic
- CYP3A4
Resistance to protease inhibitors
- ___ genetic barrier of antiretrovirals
- Mutations can be in active site or far away
- Protease inhibitors bind tightly to protease
- Natural substrates have variable, less tight binding
- Resistance mutations have ___ effect on PI than natural substrate
- Multiple mutations are usually needed to confer high level resistance
- Highest
- greater
PI - AEs
- ___
- insulin resistance and ___
- lipodystrophy
- elevated liver function tests
- Possible increased bleeding risk
- Drug-drug interactions
- hyperlipidemia
- diabetes
Treatment: Preferred Regimens
Biktarvy
- bictegravir ( ___ )
- emtricitabine ( ___ )
- tenofovir alafenamide ( ___ )
- INI
- NRTI
- NRTI
Treatment: Preferred Regimens
Triumeq
- dolutegravir ( ___ )
- abacavir ( ___ )
- lamivudine ( ___ )
- INI
- NRTI
- NRTI
Treatment: Preferred Regimens
Dovato
- dolutegravir ( ___ )
- lamivudine ( ___ )
- INI
- NRTI
Treatment: Preferred Regimens
Genvoya
- elvitegravir/ ___ ( ___ and booster)
- emtricitabine ( ___ )
- tenofovir alafenamide ( ___ )
- cobicistat, INI
- NRTI
- NRTI
Long-acting injectable therapies
Cabotegravir ( ___ ) and ___ (NNRTI) is administered as monthly or bimonthly injections
Lenacapavir is a capsid inhibitor developed by Gilead with biannual injection for HIV treatment and prevention.
- Binds on the HIV capsid p24 protein
- Interferes with virus replication by preventing virus assembly of the capsids into a stable structure.
- First in class medication
- INI
- rilpivirine
