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RING-EXPANDED NUCLEOSIDES (RENS) AS ANTITUMOR AGENTS  <ul><li>Dr. Ram Hosmane </li></ul><ul><li>University of Maryland (UM...
It All Started with  the Observed Antiviral Activity of RENS! <ul><li>RENs are Potent Inhibitors of  Flaviviridae  Helicas...
RENs are also Potent Inhibitors of HIV Replication U M B C
What Is The Mechanism of HIV Inhibition by RENS? <ul><li>HIV Does Not Have Its Own Helicase! </li></ul><ul><li>RENs Do Not...
RENs NZ-46 & NZ-51   Both Inhibit Human RNA Helicase DDX3 U M B C
DDX3 Belongs to the Family of Human RNA Helicases (HRHs) <ul><li>HRHs unwind the double-stranded RNA/DNA </li></ul><ul><li...
Relationship Between DDX3 and Cancer <ul><li>DDX3  is involved in diverse cellular processes: </li></ul><ul><ul><ul><li>mR...
DDX3 Levels in Patient Samples
Molecular Structiure of Human RNA Helicase DDX3 U M B C <ul><li>73 kD protein </li></ul><ul><li>Two distinct domains:  </l...
Molecular Modeling:  Energy-Minimized Structure of  DDX3 Complexed with NZ-51 U M B C
A Close-Up View (5 Å Radius from Ligand) of DDX3:NZ-51 Complex U M B C
Effect of NZ51 on Normal Immortalized Breast  Cell Lines U M B C
Effect of NZ51 on Breast Cancer Cell Lines U M B C
NZ51 Induces Cell Death Under Hypoxic Condition U M B C
NZ51 Decreases Tumor Growth  in vivo U M B C
Effect of NZ51 on Normal Immortalized Lung Cell Line  and Lung Cancer Cell Lines U M B C
Effect of NZ51  on Leukemia Cell Lines U M B C
ACKNOWLEDGMENTS <ul><li>Dr. Ning Zhang, UMBC </li></ul><ul><li>Dr. Venu Raman, Johns Hopkins Medical School </li></ul><ul>...
THE END THANK YOU! U M B C
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Hosame Gcc09 Retreat 15min 100209

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University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

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Hosame Gcc09 Retreat 15min 100209

  1. 1. RING-EXPANDED NUCLEOSIDES (RENS) AS ANTITUMOR AGENTS <ul><li>Dr. Ram Hosmane </li></ul><ul><li>University of Maryland (UMBC) </li></ul><ul><li>1000 Hilltop Circle, Baltimore, MD 21250 </li></ul>U M B C
  2. 2. It All Started with the Observed Antiviral Activity of RENS! <ul><li>RENs are Potent Inhibitors of Flaviviridae Helicases: W est Nile Virus (WNV), Hepatitis C Virus (HCV) and Japanese Encephalitis Virus (JEV) </li></ul>U M B C <ul><li>Increasing In Vitro Activity with Increasing Chain Length </li></ul><ul><li>Micromolar or Submicromolar IC 50 when n=17 </li></ul>
  3. 3. RENs are also Potent Inhibitors of HIV Replication U M B C
  4. 4. What Is The Mechanism of HIV Inhibition by RENS? <ul><li>HIV Does Not Have Its Own Helicase! </li></ul><ul><li>RENs Do Not Inhibit HIV Reverse Transcriptase (HIV RT)! </li></ul><ul><li>HIV Is Speculated to Exploit Human RNA Helicase DDX3 for Transportation of Lengthy, Unspliced, and Unedited HIV RNA Genome Out of the Cell Nucleus Into the Cytoplasm </li></ul><ul><li>Do RENs Inhibit Human Helicase DDX3? </li></ul>U M B C
  5. 5. RENs NZ-46 & NZ-51 Both Inhibit Human RNA Helicase DDX3 U M B C
  6. 6. DDX3 Belongs to the Family of Human RNA Helicases (HRHs) <ul><li>HRHs unwind the double-stranded RNA/DNA </li></ul><ul><li>Utilize energy derived from NTP hydrolysis </li></ul><ul><li>Two largest HRH families: DEAD-box (DDX = asp-glu-ala-asp) & DEAH box </li></ul><ul><li>Contain eight conserved motifs </li></ul>U M B C
  7. 7. Relationship Between DDX3 and Cancer <ul><li>DDX3 is involved in diverse cellular processes: </li></ul><ul><ul><ul><li>mRNA export, translation, cell growth control </li></ul></ul></ul><ul><li>DDX3 is overexpressed in breast epithelial cells: </li></ul><ul><ul><ul><li>exposure to a cancer-causing agent </li></ul></ul></ul><ul><li>DDX3 promotes: </li></ul><ul><ul><ul><li>growth, proliferation and neoplastic transformation of breast epithelial cells </li></ul></ul></ul>U M B C
  8. 8. DDX3 Levels in Patient Samples
  9. 9. Molecular Structiure of Human RNA Helicase DDX3 U M B C <ul><li>73 kD protein </li></ul><ul><li>Two distinct domains: </li></ul><ul><li>1. ATP-binding </li></ul><ul><li>2. Helicase </li></ul>
  10. 10. Molecular Modeling: Energy-Minimized Structure of DDX3 Complexed with NZ-51 U M B C
  11. 11. A Close-Up View (5 Å Radius from Ligand) of DDX3:NZ-51 Complex U M B C
  12. 12. Effect of NZ51 on Normal Immortalized Breast Cell Lines U M B C
  13. 13. Effect of NZ51 on Breast Cancer Cell Lines U M B C
  14. 14. NZ51 Induces Cell Death Under Hypoxic Condition U M B C
  15. 15. NZ51 Decreases Tumor Growth in vivo U M B C
  16. 16. Effect of NZ51 on Normal Immortalized Lung Cell Line and Lung Cancer Cell Lines U M B C
  17. 17. Effect of NZ51 on Leukemia Cell Lines U M B C
  18. 18. ACKNOWLEDGMENTS <ul><li>Dr. Ning Zhang, UMBC </li></ul><ul><li>Dr. Venu Raman, Johns Hopkins Medical School </li></ul><ul><li>Dr. Martin Edelman, UMGCC </li></ul><ul><li>Dr. Angelika Burger, UMGCC </li></ul><ul><li>Dr. Mariola Sadowska, UMGCC </li></ul><ul><li>FUNDING </li></ul><ul><li>NIH Grant (# 1 R01 GM087738-01A1) </li></ul>
  19. 19. THE END THANK YOU! U M B C

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