1. “The sovereign Lord has filled me with his spirit. He has chosen me and sent me to bring good news to the poor, To heal the broken-hearted, to announce release to the captives, And freedom to those in prison. He has sent me to proclaim that the time will come When the Lord will save his people and defeat their enemies” Excerpt from the passage from Isaiah 61 read at the inauguration of Jean Bertrand Aristide

2. Throughout the class we will explore how we can use basic science to guide the design of new treatments for disease

3. http://www.avert.org/his81_86.htm A retrovirus causes AIDS A series of basic science discoveries have given us substantial insight into the cause of AIDS Retroviruses reverse the central dogma

4. Potential Therapies- Life Cycle of HIV-1 Let’s start where the field started: with reverse transcriptase

5. Here’s the enzyme synthesizing a DNA complement To the HIV RNA genome

6. Let’s zoom in on this step

7. RT adds a DNA nucleotide complementary to Each RNA nucleotide in the HIV genome

8. Here’s the chemistry: http://www.avert.org/his81_86.htm

9. If we get rid of this hydroxyl group, the enzyme can’t add another nucleotide http://www.avert.org/his81_86.htm

10. AZT (azidothymidine) is an exact match to the T nucleotide but without the hydroxyl group!

11. http://www.avert.org/his81_86.htm The result…

12. http://www.avert.org/his81_86.htm How did we get here?

13. The success of sulfa drugs in inhibiting bacterial metabolism inspired two scientists at Wellcome Research Labs to investigate other metabolic pathways Nobelprize.org and www.chemheritage.org Gertrude Elion George Hitchings

14. The success of sulfa drugs in inhibiting bacterial metabolism inspired two scientists at Wellcome Research Labs to investigate other metabolic pathways Nobelprize.org and www.chemheritage.org Gertrude Elion George Hitchings They started just as people figured out That DNA is the genetic material!

15. They looked for derivatives of nucleotides That inhibited synthesis of DNA and RNA Nobelprize.org and www.chemheritage.org Gertrude Elion George Hitchings

16. They looked for derivatives of nucleotides That inhibited synthesis of DNA and RNA Nobelprize.org and www.chemheritage.org Gertrude Elion George Hitchings Suppresses immune system (first kidney transplants) First drugs against leukemia

17. When Hitchings became Vice President for Research Elion was promoted to Head of the Department of Experimental Therapy (without a Ph.D!) and her group continued to explore these pathways Nobelprize.org and www.chemheritage.org Gertrude Elion George Hitchings

18. When Hitchings became Vice President for Research Elion was promoted to Head of the Department of Experimental Therapy (without a Ph.D!) and her group continued to explore these pathways Nobelprize.org and www.chemheritage.org Gertrude Elion George Hitchings Treats gout and being tested against the Leishmania parasite They also explored mechanism of action Of acyclovir and its affect on Herpes virus

19. For all this hard work …. Nobelprize.org and www.chemheritage.org Gertrude Elion George Hitchings

20. http://www.avert.org/his81_86.htm Others followed their lead

21. http://www.avert.org/his81_86.htm Jerome Horwitz--first synthesized AZT in 1964 as a possible anticancer drug

22. http://www.avert.org/his81_86.htm But it failed!

23. http://www.avert.org/his81_86.htm The first treatment option: a time line Februrary 1985 Scientists at National Cancer Institute and at Burroughs Wellcome Collaborate to study effect of AZT on HIV in cell culture

24. http://www.avert.org/his81_86.htm The first treatment option: a time line Februrary 1985 Scientists at National Cancer Institute and at Burroughs Wellcome Collaborate to study effect of AZT on HIV in cell culture September 1986 Early clinical trials showed that AZT slowed down the attack of HIV.

25. http://www.avert.org/his81_86.htm The first treatment option: a time line Februrary 1985 Scientists at National Cancer Institute and at Burroughs Wellcome Collaborate to study effect of AZT on HIV in cell culture September 1986 Early clinical trials showed that AZT slowed down the attack of HIV. The AZT clinical trial: one group of patients received AZT and the other received placebo. At the end of six months, only one patient in the AZT group was dead, whilst there were 19 deaths among the placebo group. The clinical trial was stopped early, because it was thought to be unethical to deny the patients of the placebo groups a better chance of survival. Fischl M. A., et al. (1987)''The Efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex, a double-blind, placebo-controlled trial', The New England Journal Of Medicine, Vol. 317: 185-191, Number 4 FDA approved March 20, 1987!

26. http://www.avert.org/his81_86.htm The first treatment option: a time line August 1989 First large clinical trial of AZT in asymptomatic patients showed that it slowed progression of disease The day after the press conference, Burroughs Wellcome stock rose 32%.

27. http://www.avert.org/his81_86.htm The first treatment option: a time line August 1989 First large clinical trial of AZT in asymptomatic patients showed that it slowed progression of disease The day after the press conference, Burroughs Wellcome stock rose 32%. The high price of AZT angered many people; a year's supply cost ~$7,000 In September, the cost of the drug was cut by 20%.

28. Thus the early response of HIV to AZT was superb Does this sound familiar? Does it make you worried?

29. The bad news came quickly and was not unexpected

31. Mutations altering amino acids In the AZT binding site of Reverse transcriptase Led to resistance

32. By the early 1990s resistance was a serious problem

33. How do we get around this???

34. http://www.avert.org/his81_86.htm Same concept, new drugs! InosineddI Used in patients by October 1989

35. http://www.avert.org/his81_86.htm Same concept, new drugs! Cytodine ddC FDA approved Summer 1991

36. http://www.avert.org/his81_86.htm If you treat patients with ddI or ddC ALONE What will happen? Cytodine ddC FDA approved Summer 1991

37. http://www.avert.org/his81_86.htm So how do you get around this?? Cytodine ddC FDA approved Summer 1991

38. http://www.avert.org/his81_86.htm If it worked for TB…..

39. http://www.avert.org/his81_86.htm September 1995 Two clinical trials, the Delta trial and the ACTG175 trial, showed that combinations of AZT with ddI or ddC were more effective than AZT alone in delaying disease progression and prolonging life. If it worked for TB…..

40. Retroviruses. CSHL Press Fig. 13-10 Chemists keep Tinkering with nucleotides To make new drugs

41. www.web-books.com/.../ Infectious/AIDS_Treat.htm