-
NRTI's
- nucleoside analog reverse transcriptase inhibitors
- 1st gen nucleoside analogs
-
example of a NRTI
AZT (ZDV)
-
main problem 1st gen nucleoside analogs
interfere w/ mtDNA replication leading to toxicity
-
MOA of nucleoside analogs
- DNA chain terminator -> lack 3' hydroxyl which prevents sugar-phophate linking
- mitochondrial poison
-
NNRTI's
- non-nucleoside reverse transcriptase inhibitors
- "butterfly drugs" - hydrophobic wings/flanks
-
NNRTI MOA
non-competitively inhibits reverse transcriptase by binding to a "pocket" adjacent to the active site ,changing protein shape
-
problem w/ 1st gen NNRTI
one mutation confers extensive resistance
-
1st gen NNRTI SE's
- hypersensitivity
- hepatitis/rash
-
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
-
problems w/ 1st gen protease inhibitors
- big
- lipophilic
- poor solubility
- tolerability
-
protease inhibitor SE's
- laxativesÂ
- nausea, bloating, diarrhea
- high blood lipids, hyperglycemia
-
2nd gen protease inhibitors improve on...
- solubility & tolerability
- flexibility
-
zidovudine (AZT)
- first HIV drug approved
- analog of thymidine
- originally developed as anti-leukemia drug
-
NRTI pharmacophore feature
lacks 3' hydroxyl group
|
|
