Development of AIDS therapeutics targeting the HIV-Tat host cofactor P-TEFb

• Project/Area Number: 19590116
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: FUKAZAWA Hidesuke National Institute of Infectious Diseases, 生物活性物質部, 室長 (10218878)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2008: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2007: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: HIV-1 / P-TEFb / Tat / Cyclin T / CDK9 / Cyclin K / BRD4

Research Abstract

HIV-1 Tat及びTat の宿主cofactor P-TEFbを標的とした薬剤の研究を行った。Cyclin KはTat-responsive motifを欠くため、Tat/P-TEFb/TAR複合体形成を阻害する可能性がある。Cyclin K をHIV-1と293T細胞に発現させるとCyclin Kの発現量に応じてHIV-1産生は低下し、Cyclin Kはレンチウイルス複製の負の調節因子であることがわかった。またMT-4細胞をHIV-1耐性にするcDNA を探索し、BRD4 C末端領域(BRD4-CTD)を得た。BRD4-CTDはTat依存性のLTRからの転写を選択的に抑制した。以上はHIV-1複製がCyclin T1を含むP-TEFb に強く依存すること、またCyclin T1のBRD4結合領域が抗HIV薬の新規標的となることを示す。

Research Products

• [Journal Article] Identification of the P-TEFb complex-interacting domain of Brd4 as an inhibitor of HIV-1 replication by functional cDNA library screening in MT-4 cells. (2008)
  • Author(s): Urano, E., Kariya, Y., Futahashi, Y., Ichikawa, R., Hamatake, M., Fukazawa, H., Morikawa, Y., Yoshida, T., Koyanagi, Y., Yamamoto, N., and Komano, J.
  • Journal Title: FEBS Letters 582 Pages: 4053-4058
  • Peer Reviewed
• [Journal Article] Cyclin K/CPR4 inhibits primate lentiviral replication by inactivating Tat/P-TEFb-dependent LTR transcription. (2008)
  • Author(s): Urano, E., Shimizu, S., Futahashi, Y., Hamatake, M., Morikawa, Y., Takahashi, N., Fukazawa, H., Yamamoto, N., and Komano, J.
  • Journal Title: AIDS 22 Pages: 1081-1083
  • Peer Reviewed
• [Journal Article] Cyclin K/CPR4 inhibits primate lentiviral replication by inactivating Tat/positive transcription elongation factor b-dependent long terminal repeat transcription (2008)
  • Author(s): Urano, E., et al.
  • Journal Title: AIDS 22 Pages: 1081-1083
  • Peer Reviewed
• [Journal Article] Identification of the P-TEFb complex-interacting domain of Brd4 as an inhibitor of HIV-1 replication by functional cDNA library screening in MT-4 cells (2008)
  • Author(s): Urano, E., et al.
  • Journal Title: FEBS Lett 582 Pages: 4053-4058
  • Peer Reviewed
• [Journal Article] Cyclin K/CPR4 inhibits primate lentiviral replication by inactivating Tat/P-TEFb-dependent LTR transcription. (2008)
  • Author(s): Urano, E., et. al.
  • Journal Title: AIDS (in press)
  • Peer Reviewed
• [Journal Article] Gamma-herpesviruses and cellular signaling in AIDS-associated malignancies. (2007)
  • Author(s): Noguchi, K., Fukazawa, H., Murakami, Y., Takahashi, N., Yamagoe, S., and Uehara, Y.
  • Journal Title: Cancer Science 98 Pages: 1288-1296
  • Peer Reviewed
• [Journal Article] Gamma-herpesviruses and cellular signaling in AIDS associated malignancies. (2007)
  • Author(s): Noguchi, K., et. al.
  • Journal Title: Cancer Science 98 Pages: 1288-1296
  • Peer Reviewed