Brian Grieb October 27, 2004 Future Directions in Chemistry

1. M. tuberculosis Drug Development New Inhibitor of Cell Wall Biosynthesis Brian Grieb October 27, 2004 Future Directions in Chemistry

2. Why Drug Development? • What is TB? • infection of the lungs by • Mycobacterium tuberculosis • Statistics • in 2002, over 2 million died • new infection every second • Drug Resistant Strains • 10% of cases are MDR-TB • 7.9% “super strains” • - no new drug in 40 years • November 1998, sequenced TB genome • - ability to create new drugs

3. M. tuberculosis Cell Wall • Protective Properties • Required for growth • and proliferation of bacteria • Construction • Current Drugs • - Isoniazid • - Rifampicin • - Ethambutol • New target

4. Galf Polysaccharide Polymer • Why Galf polymer? • Synthesis of polymer • No known inhibitor of UDP Galf-transferase

5. Enzyme Inhibitor: Iminosugars • Known inhibitors of • carbohydrate enzymes • Definition: • replace ring O with N • replace ring O with C • and one ring C with N • Which C should be • replaced to inhibit transferase? Inhibits the mutase

6. Transition State • Proposed transition state • Partial charge • Replace anomeric C • with N

7. Inhibitor Development Actual Sugar Ideal Inhibitor UNSTABLE Proposed Inhibitor

8. Inhibitor Synthesis

9. Synthesis Yield 24% Yield 13% Yield

10. Inhibiting Ability • Results • Significance • Possible explanation • Dual function • of enzyme 40% at 8mM 50% at 4.8mM 6C 5C 6C

11. Future Directions • Enhance inhibitors with UDP mimic • Continue drug development for TB • Find three other protein contributing to cell wall production • Find gene sequence responsible for latency • The World Health Organization wants a new TB drug • on the market by 2006 and a second by 2012.

12. References Cole S., Deciphering the biology of Mycobacteruim tuberculosis from the complete genome sequence, Nature, June 1998, 393, 537-544. Cren S., Synthesis and biological evaluation of new inhibitors of UDP-Galf tranferase-a key enzyme in M. tuberculosis cell wall synthesis, Org. Biomol. Chem. 2004, 2, 2418-2420 Freemantle M., Inhibitors Target Key TB Enzyme, Chemical and Engineering Magazine, September 6, 2004, 12. Kremer L., Galactan Biosynthesis in Mycobacterium tuberculosis, Biological Chemistry, July 2001, 276, 28, 26430-26440. Look G., Enzyme-Catalyzed Organic Synthesis: Practical Routes to Aza Sugars and Their Analogs for use as Glycoprocessing Inhibitors, Acc. Chem. Res., 1993, 26, 182-190. Pan F., Cell Wall Core Galactofuran Synthesis Is Essential for Growth of Mycobacteria, Bacteriology, July 2001, 183, 13, 3991-3998. Scherman M., Drug Targeting Mycobaterium tuberculosis Cell Wall Synthesis: Development of a Microtiter Plate-Based screen for UDP-Galactopyranose Mutase and Identification of an Inhibitor from a Uridine-Based Library, Antimicrobial Agents and Chemotherapy, Jan. 2003, 47, 378-382. World Health Organization, Combining TB treatment with HIV testing and treatment could save live up to 500,000 HIV positive Africans every year, http://www.who.int/mediacentre/news/releases/2004/pr66/en/ World Health Organization, Drug resistant tuberculosis levels ten times higher in Eastern Europe and Central Asia, March 2004, http://www.who.int/mediacentre/new/releases/2004/pr17/print.html World Health Organization, Tuberculosis Facts Sheet, http://www.who.int/topics/tuberculosis/en/ PICTURESTB bacteria: http://www.abc.net.au/science/news/img/tb.jpg Chest X-Ray: http://www.reactivereports.com/20/images/tb.jpg Current Drugs: http://www.taacf.org/about-TB-current-drugs.htm WHO logo: http://www.who.int/about/en/ Transition State in color: http://www.rsc.org/CFmuscat/intermediate_abstract.cfm?FURL=/ej/OB/2004/B411554F/B411554F.PDF&TYP=017