1. The Captopril Story

2. The Problem Hypertension – high blood pressure can lead to heart attacks or stroke.

3. The lead compound The Brazilian Arrowhead Viper kills by causing a catastrophic fall in blood pressure. The venom does this by preventing the formation of a small protein Angiotensin II

4. Angiotensin II is a 8 amino-acid protein produced from an inactive 10 amino-acid protein Angiotensin I by the Angiotensin Converting Enzyme ACE. Angiotensin I → Angiotensin II + dipeptide The dipeptide is cut of at the Leucine-C00H end Asp Arg Val Tyr Ile His Pro Phe His Leu → Asp Arg Val Tyr Ile His Pro Phe + His Leu ACE.

5. ● The active compounds in the Venom are small proteins that inhibit ACE. ● But proteins are hydrolysed in the stomach and so cannot be taken by mouth and so would not be convenient medicines. ● We need to look at ACE to see how it can be inhibited.

6. A ACE : the blue sphere is a Zn 2+ ion.

7. HNHN NH3 + Zn 2+ A simplified representation of the active site :

8. HNHN NH3 + Zn 2+ This can accommodate the C terminal end of angiotensin I

9. HNHN NH3 + Zn 2+..which is then hydrolysed by the action of the zinc ion.

10. Solution ● All the active proteins from the snake venom had proline as the C terminal. ● An SH group was found to be effective at binding to the Zn 2+ ion ● A series of compounds were made with both of these features.

11. HS-CH 2 -CH(CH 3 )-CO-Pro HS-CH 2 -CH 2 -CO-Pro HS-CH 2 -CH 2 -CH 2 -CO-Pro Concentration to give 50% inhibition /10 -6 mol dm -3 0. 02 0.30 9.70 Which of these would you choose ?

12. HNHN NH3 + Zn 2+ This binds tightly to the active site… : so disabling the enzyme. :

13. ● Captopril passed the testing procedues. ● It was launched in 1980 and is now in widespread use.