Lecture 14 - HIV Protease Inhibitors Flashcards
Drugs work best when
Target non human factor
Any drugs that bind to multiple targets tend have
Adversities
Patients don’t want to take
HIV difficult because
Integrates its viral DNA (via RNA) into human cells
HIV protease (enzyme)
Helps virus mature
HIV protease enzyme
Homodimer
Aspartate (aspartyl) protease
Cleave long protein
Work on bonds phenyl proline or Tyr proline (Mammals don’t have this enzyme)
Good target
Enzymes
Catalyze reactions
Active site
Preferred substrates
Inhibited. Competitive / non competitive
Used to develop a virus specific drug
what do you Need to know to design an inhibitor?
active site and substrate:
HIV proteases are a type of
aspartate (aspartyl) protease.
Aspartate residues in
active site
what do 2 residues use to cleave the peptide bond in a one-step reaction?
water
HIV Protease is a homodimer formed of
2 identical amino acid chains
aspartate residues.
HIV proteases cleaves bonds between
Phenylalanine and Proline
Tyrosin and Proline
Apart from aspartate residues what other residues help position amino acid chain (S) by forming hydrophobic pockets for side chains?
S1, S2, S3 (on one chain)
and
S1’, S2’, S3’ (on the other chain)
What is the substrate?
HIV protease cleave long amino acid chain that then forms multiple smaller proteins that the HIV virus uses to replicate and infect other cells
What bond do you need to cut to cleave a protein?
Peptide bond
Lets make a drug
- Build a peptide-like backbone
- Add some bulky side groups so it fits the active site
- Design the rest of drug so it can be absorbed from a tablet
Does drug work?
3D structure of HIV protease
dimer in complex with protease inhibitor saquinavir bound at the active site
Saquinavir drug
Bind active site
Stops enzyme from working
Lots of similar drugs like this
Same peptide backbone with bulky stuff
Non comp inhibitor
Bind somewhere else
added substrate won’t remove it
Vmax unchange
Km unchange
Comp inhibitor
Binds to active site
added substrate remove it
Kmchanges
What type of inhibitor do you want the drug to be comp or non comp?
comp
on y axis Vmax won’t move on axis stays same
Downside with protease inhibitor side effects
Nausea, vomit, diarrhea
Heart problems
Interact with other drugs
HIV protease mutate cause
resistance
