1. Back to HIV Protease Actual Reaction (Hydrolysis): Water attacks the amide linkage to convert it into two products: an amine and a carboxylic acid BUT water is not reactive enough to do this on its own.

2. HIV Protease makes water more reactive An aspartic acid side chain (in the HIV protease enzyme) converts water (H 2 O) into the more reactive hydroxide ion (OH - ) and the enzyme stabilizes the transition state

3. Inhibiting HIV Protease Would prevent the hydrolysis of the polyprotein reduce the rate of HIV replication

4. Transition State Analog The geometry of the transition state is different than the geometry of the amide linkage The Inhibitor should mimic the geometry of the transition state

5. Geometry of the Amide Linkage

6. Geometry of the Transition State

7. HIV Protease Inhibitor: Crixivan

8. HIV Protease and Crixivan

10. Hydrogen Bonding keeps the E-S complex tight

11. The Impact of HIV Protease Inhibitors

13. HIV Protease Inhibitors dramatically lower the levels of HIV (viral load) in a patient’s blood Unfortunately The viral load starts increasing again within 12-18 months of starting the therapy