Anti-AIDS Flashcards
Overall HIV pathogenesis
RESTING CD4+ lymphocytes that have an avg lifespan of YEARS carrying HIV infection that outcompete
Recently infected CD4+ lymphocytes (avg lifespan of 2.2days)
4 Classes of Anti-viral Drugs
1) Drugs that BLOCK HIV ENTRY into host CD4+ Tcells [FUSION INHIBITORS] - Not first-line drugs anymore, rather SECOND-LINE
2) Drugs that BLOCK Reverse Transcriptase
3) Drugs that BLOCK Integration into host genome via INTEGRASE
4) Drugs that BLOCK Proteolytic activity to make functional, cleaved subunits via PROTEASE
Mechanism of Viral entry
1) Gp120 protein (VIRAL SURFACE) recognized by CD4 + Coreceptors (CCR5 or CXCR4) -> Gp120 gets stripped off
* Gp41 is bound/protected by Gp120 - Does not uncoil unless needed
2) Gp120 Removed -> Gp41 UNCOILS -> Sticks end into nearby CD4 cells
3) Gp41 RECOILS - Refolding of Gp41 [re-associates N/C termini] -> Reels in CD4
4) Membrane fusion
DRUG CLASS 1: Fusion Inhibitor
What is its mechanism?
Synthetic Amino Acid that mimics C-terminus of GP41 -> Prevents refolding/recoiling of Gp41 -> CD4 does NOT get reeled in
Name the FUSION INHIBITOR anti-AIDS drugs (2)
1) Enfuvirtide - gp41 targeting
2) Maraviroc - Hu CCR5 targeting
Why did ENFUVIRTIDE become a 2nd-line Anti-AIDS drug?
1) PHARMACODYNAMICS: High first pass metabolism and thus requires 2 subcutaneous injections/day
2) SIDE EFFECT: Skin reaction at the site of injection + Greater pneumonia incidence
3) RESISTANCE: Mutation appearance at the N-terminus of gp41 (binding site of enfuvirtide)
What is the specific mechanism of ENFUVIRTIDE?
SYNTHETIC C-peptide sequence that competitively binds to N-terminal region -> Prevents N/C termini re-association [recoiling] of gp41 -> Prevents FUSION of virus and CD4+
What is the specific mechanism of MARAVIROC?
Targets HUMAN CCR5 Co-receptor of CD4+ Tcells -> gp120 can not recognize -> Blocks HIV entry
What is the basis of a drug targeting a human receptor? (Maraviroc)
Targeting human components: Masks the human receptor so that the HIV virus can never find it
Caveat of Maraviroc Usage
Only works for CCR5-TROPIC HIV ISOLATES
[Diagnostic test: determine by PCR]
If the HIV isolates utilize CCR5 and NOT CXCR4 as the co-receptor
- If HIV isolate mutates to NON-CCR5 tropic, maraviroc is NO LONGER effective, especially in LATE stages *
How is MARAVIROC metabolized? What does this implicate?
Metabolized by p450 enzymes -> p450 inducers and inhibitors can influence maraviroc levels by increasing or decreasing its half life
- Take caution if pt is taking any other drugs that utilize p450 enzymes for metabolism *
What is the mechanism of resistance developing to MARAVIROC?
Mutant HIV strains that use CXCR4 (not CCR5) to gain entry into CD4+ T cell
DRUG CLASS 2: Name the reverse transcriptase inhibitors (4).
NON-NUCLEOSIDE
1) Efavirenz
2) Etravirine
NUCLEOSIDE:
1) Emitricitabine
2) Tenofovir
Activities of HIV Reverse Transcriptase (2)
ACTIVITY 1: SYNTHETASE [p66 Reverse Transcriptase] -
Uses tRNA (Lys) to serve as 3’OH primer -> Synthesizes DNA Strand
ACTIVITY 2: RNA-ase [RNAseH] -
Chews up RNA template strand but leaves a little bit of RNA to serve as PRIMER for second DNA strand synthesis
RESULT: dsDNA HIV DNA genome is created and can now become integrated into host
Measurements of HIV progression
1) CD4+ Count (monitors pt’s immune system status + susceptibility to opportunistic infn of virus)
2) HIV-1 RNA levels (most effective at monitoring therapeutic intervention) - RNA levels drop 10-100x within 1wk of treatment (protease, RT inhibitor)
What are the 2 nucleoside reverse transcriptase inhibitors?
Emtricitabine
Tenofovir
What is the specific mechanism of the nucleoside reverse transcriptase?
Emtricitabine + Tenofovir are nucleoside analogs that bind active site of HIV RT - do NOT have 3’OH -> Immediately terminates chain elongation
SUICIDE SUBSTRATES: 3’OH of growing DNA strand attacks alpha phosphate of drug -> No subsequent 3’OH -> CHAIN STOPS HERE
What does it mean that EMTRICITABINE + TENOFOVIR are “pro-drugs”?
They are NUCLEOSIDES = no phosphates (bulky negative charge that would impede entry into cells)
Nucleoside or NMP [Pro-drug] -> Facilitate entry -> Pt’s kinases phosphorylate drug [Drug] -> Act as nucleoside reverse transcriptases
What confers selectivity of EMTRICITABINE + TENOFOVIR for HIV RT rather than human DNA polymerase?
HIV RT is a “sloppier enzyme” - Can bind WELL to the nucleoside drug
Human nuclear DNA polymerases - Does NOT bind well to the drug
How is the half life of EMTRICITABINE + TENOFOVIR extended?
Phosphorylation by pt’s enzymes -> Active drug form [negatively charged] is now trapped inside the cell
What is the most common adverse side effect of EMTRACITABINE + TENOFOVIR? What is the mechanism of this side effect?
Muscle soreness/weakness [LACTIC ACIDOSIS] -
Generally, NRTIs are selective for HIV RTs EXCEPT for MITOCHONDRIAL POLYMERASES -> Lactic acidosis
What is the mechanism of resistance of EMTRICITABINE + TENOFOVIR?
Mutation in the active site of HIV RT
Each NRTI has UNIQUE profile of resistance mutations
Classify the chemical composition of EMTRICITABINE.
Fluorinated analog of lamivudine (one of the first NRTIs)
*Fluorination - decreases its degradation -> increases its half life
Classify the chemical composition of TENOFOVIR.
Adenosine + Phosphate (AMP analog)
- Technically NUCLEOTIDE reverse transcriptase inhibitor *
Mechanism of TENOFOVIR entry from its inactive prodrug form to active form inside cells.
Drug AMP analog (pro-drug form) gets into intestinal lumen -> Protective groups are removed -> Enters cells via ENDOCYTOSIS -> Pt’s kinases phosphorylate to triphophosphate
Selective advantage of TENOFOVIR’s monophosphate moiety, compared to other NRTIs
Phosphate group does limit its entry into cells BUT it also OVERCOMES rate limiting phosphorylation step in CD4+ T cells
Overcoming rate-limiting phosphorylation step»_space; Cost of limited drug entry into cells
Combo Pill: EMTRICITABINE + TENOFOVIR
TRUVADA
Other advantages of TENOFOVIR:
1) Interacts little with P450 -> Little side effects
2) Develops very little resistance slowly: TENOFOVIR retains activity even if there is resistance to other NRTIs
What are the 2 non-NRTIs?
Efavirenz
Etravirine
Mechanism of EFAVIRENZ + ETRAVIRINE:
non-NRTIs = ALLOSTERIC RT inhibitors
Mechanism: Bind to site adjacent to RT active site -> Induces conformational change that blocks RT activity
Do EFAVIRENZ + ETRAVIRINE require phosphorylation for activity like EMTRICITABINE/TENOFOVIR?
NO - Do not require cellular activation (phosphorylation) -> Diffuses directly into cells
How are EFAVIRENZ + ETRAVIRINE metabolized?
P450 enzymes - Do have drug interaction (Caution with other drugs that may inhibit or induce P450 activity)
Explain the occurrence of Methadone withdrawal when pt is on a non-NRTI
non-NRTI (nevirapine not tested) INDUCES p450 (CYP3A) activity -> Metabolizes methadones a lot more quickly -> Experiences methadone withdrawal symptoms
ETRAVIRINE specific property to deal with the emergence of resistance
Designed to retain persistent activity despite mutations in HIV RT active site by “STRATEGIC FLEXIBILITY” -
Drug has the key AA sequences to fit the HIV RT active site, but can still accommodate 3-4 mutations by “wiggling [torsional]/jiggling[positional]”
DRUG CLASS 3: Name the viral integrase inhibitors (3).
-“gravir”s
Raltegravir
Elvitegravir
Dolutegravir
The most common first-line anti-AIDS drugs fits into which class of drugs?
Viral Integrase Inhibitors (R,E,D)
Functions of viral integrase:
1) Cleaves off a few bases of viral DNA -> Creates recessed 3’ OH ends
2) Holds onto clipped viral DNA -> Carries it to host genome -> Positions viral DNA so that it can become incorporated
3) Nicks in host genome (with viral DNA incorporated) - Repaired by host DNA repair system
What is the mechanism of RALTEGRAVIR + ELVITEGRAVIR + DOLUTEGRAVIR?
Binds to Mg2+ in active site of viral DNA/Integrase complex
Result: 3’OH ends get “kicked away” or displaced away from the reactive center
How does RALTEGRAVIR get metabolized?
NOT by p450 - No drug/drug interaction
By GLUCURONIDATION
Combination pill: EMTRICITABINE + TENOFOVIR + ELVITEGRAVIR + COBICISTAT
STRIBILD
What is the function of COBICISTAT in STRIBILD?
BOOSTING AGENT (not anti-viral itself): Inhibits CYP3A4 metabolism, by which ELVITEGRAVIR is metabolized -> Increases its half-life
How is ELVITEGRAVIR metabolized?
CYP3A4 p450 enzyme
Why is DOLUTEGRAVIR the most preferred viral integrase inhibitor drug?
Does NOT require BOOSTING agent: COBICISTAT
Combination Pill: DOLUTEGRAVIR + ABACAVIR + LAMIVUDINE
TRIUMEQ
What is another desired property of DOLUTEGRAVIR regarding resistance?
Develops little resistance very slowly:
Retains its activity even if pt acquires resistance to other viral integrase inhibitors
CLASS 4: Name the 3 protease inhibitor drugs
-“avir”s
Ritonavir
Atazanavir
Darunavir
Function of HIV Protease:
Cleave long polypeptides into active subunits (RT, protease, integrase, structural proteins, etc.)
How is selectivity conferred to viral protease inhibitors?
Viral Proteases: Asp protease that acts as a DIMER to form the catalytic site
Hu Proteases: Asp protease that acts as a MONOMER
Viral protease inhibitors: Selective for dimer form
Mechanism of RITONAVIR + ATAZANAVIR + DARUNAVIR?
Analog of viral protease TRANSITION STATES [states that bind the long polypeptide substrate the best]
What values indicate the success of viral protease inhibitor therapy?
Lowered plasma RNA levels (100-1000x)
Undetectable HIV RNA levels when combined with 2 nucleoside analogs
Adverse effects of RITONAVIR + ATAZANAVIR + DARUNAVIR
1) Body fat distribution changes - Lipodystrophy + Pseudo-Cushing’s
2) Hyperlipidemia
3) Worsening glycemic control in diabetic pts
Which is the most preferred viral protease inhibitor? Why?
DARUNAVIR -
Retains its activity even though pt develops resistance to the other viral protease inhibitors
Combopill: DARUNAVIR + COBICISTAT (literature will sometimes refer to it as RITONAVIR-boosting)
PREZCOBIX
Cobicistat: Inhibits cytochrome p450 enzyme metabolism of darunavir -> increases half life
Combopill: RIPLIVERINE (NNRTI) + EMTRICITABINE + TENOFOVIR
Truvada + Ripliverine = ?
COMPLERA
