antiviral med chem Flashcards

Question

NNRTIs

Answer 1

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

Answer 2

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

Answer 3

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)

Answer 4

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

Answer 5

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

Answer 6

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**

Answer 7

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

Answer 8

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

Answer 9

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

Answer 10

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

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

``` 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 ```

Answer 19

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

Answer 20

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

Answer 21

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

Answer 22

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

Answer 23

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

Answer 24

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

Answer 25

DRV/r (QD) + TDF/FTC