PHRD5915 Drug Design Lecture 12 - Pathogen Drug Targets

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  1. NRTI's
    • nucleoside analog reverse transcriptase inhibitors
    • 1st gen nucleoside analogs
  2. example of a NRTI
    AZT (ZDV)
  3. main problem 1st gen nucleoside analogs
    interfere w/ mtDNA replication leading to toxicity
  4. MOA of nucleoside analogs
    • DNA chain terminator -> lack 3' hydroxyl which prevents sugar-phophate linking
    • mitochondrial poison
  5. NNRTI's
    • non-nucleoside reverse transcriptase inhibitors
    • "butterfly drugs" - hydrophobic wings/flanks
    non-competitively inhibits reverse transcriptase by binding to a "pocket" adjacent to the active site ,changing protein shape
  7. problem w/ 1st gen NNRTI
    one mutation confers extensive resistance
  8. 1st gen NNRTI SE's
    • hypersensitivity
    • hepatitis/rash
  9. HIV protease inhibitor MOA
    • competitively inhibit HIV protease by mimicking the poly-protein cleavage site -> resulting virion is immature, dysfunctional, non-infectious, & rapidly cleared from the body
    • blocks infectivity at late stage
    • peptidomimetic
  10. problems w/ 1st gen protease inhibitors
    • big
    • lipophilic
    • poor solubility
    • tolerability
  11. protease inhibitor SE's
    • laxatives 
    • nausea, bloating, diarrhea
    • high blood lipids, hyperglycemia
  12. 2nd gen protease inhibitors improve on...
    • solubility & tolerability
    • flexibility
  13. zidovudine (AZT)
    • first HIV drug approved
    • analog of thymidine
    • originally developed as anti-leukemia drug
  14. NRTI pharmacophore feature
    lacks 3' hydroxyl group
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PHRD5915 Drug Design Lecture 12 - Pathogen Drug Targets
2014-05-12 16:53:00
Pathogen Drug Targets

Pathogen Drug Targets
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