2002 Fiscal Year Annual Research Report

新規の抗HIV剤の基礎的研究・デザイン・開発

Research Project

Project/Area Number	14207025
Research Institution	Kumamoto University
Principal Investigator	満屋裕明熊本大学, 医学部, 教授 (20136724)
Keywords	HIV / 多剤耐性 / プロテアーゼ阻害剤 / Gaq / ケモカイン / CCR5 / spirodiketopiperazine誘導体 / LD78β
Research Abstract	新規のプロテアーゼ阻害剤(PI),UIC94003/TMC126は強力な抗HIV活性を示し、殆ど全ての既存のPIと交差耐性を認めない事、またその機序がUIC94003とプロテアーゼの活性部位を形成するアミノ酸の主鎖との強固な水素結合形成にあることを示した(Yoshimura ＆ Mitsuya, J. Virol.76:1349-1358,2002)。他方、HIVのPI耐性発現機序についても検討、耐性獲得にcleavage sites以外のGag領域でのアミノ酸変異が重要である事を初めて示した(Gatanaga ＆ Mitsuya, JBC 277:5952-5961,2002)。又、多剤耐性発現に関与する逆転写酵素のQ151M変異が、増殖能の低下した中間体(HIV_Q151L>)を介して発現する可能'性を示した。(Matsumi ＆ Mitsuya, AIDS, in press)。一方、新規CCR5阻害剤のspirodiketopiperazine誘導体(e. g.,E913)は多剤耐性株を含むR5株に対して強力な抗ウイルス効果を発揮(Maeda ＆ Mitsuya, JBC 276:35194-35200, 2001)、更に、活性が約100倍強力で経口投与可能な新規の誘導体(AK602)を同定し臨床開発を進めている。又、ヒトMIP-1αの変異体,LD78βのNH_2末端の6個のアミノ酸をAlaに置換した組換体を作成、シグナル誘導能と抗HIV活性の構造活性連関について検討、そのようなアミノ酸置換がLD78βのCCR5を介したシグナル誘導能には変化を与えず、抗HIV活性のみを改善させること示し、ケモカイン阻害と抗HIV活性が分離できることを初めて明らかにした(Miyakawa ＆ Mitsuya, JBC 277:4649-4655, 2002)。

Research Products
(6 results)

All Other

All Publications (6 results)

[Publications] Matsumi, S., Mitsuya H.et al.: "Pathways for the emergence of multidideoxynucleoside -resistant human immuriodeficiency virus type 1 variants"AIDS. (in press). (2003)
[Publications] Tamamura, H., Mitsuya H.et al.: "Reduction of peptide character of HIV protease inhibitors that exhibit nanomolar potency against multi-drug resistant HIV-1 strains"J. Med. Chem. (in press). (2003)
[Publications] Kawamura, T., Mitsuya, H.et al.: "HIV infected dendritic cells impair T cell function : reversal of defects by soluble CD4, but not by antiretroviral drugs"J. Immunol.. (in press). (2003)
[Publications] Yoshimura K., Mitsuya H.et al.: "UIC-64003 : a potent protease inhibitor (PI) that inhibits multi-PI-resistant HIV-1 replication in. vitro"J. Virol.. 76. 1349-1358 (2002)
[Publications] Miyakawa T.Mitsuya, H.et al.: "Identification of amino acid residues critical for LD78β (a variant of human macrophage inflammatory protein-1α) binding to CCRS and inhibition of R54 HIV-1 replication"J. Biol. Chem.. 277. 4649-4655 (2002)
[Publications] Gatanaga H., Mitsuya H.et al.: "Amino acid substitutions in non-cleavage sites of the gag region are indispensable for high level HIV-1 resistance to protease inhibitors"J. Biol. Chem.. 277. 5952-5961 (2002)

2002 Fiscal Year Annual Research Report

新規の抗HIV剤の基礎的研究・デザイン・開発

Principal Investigator

満屋 裕明 熊本大学, 医学部, 教授 (20136724)

Research Products

[Publications] Matsumi, S., Mitsuya H.et al.: "Pathways for the emergence of multidideoxynucleoside -resistant human immuriodeficiency virus type 1 variants"AIDS. (in press). (2003)

[Publications] Tamamura, H., Mitsuya H.et al.: "Reduction of peptide character of HIV protease inhibitors that exhibit nanomolar potency against multi-drug resistant HIV-1 strains"J. Med. Chem. (in press). (2003)

[Publications] Kawamura, T., Mitsuya, H.et al.: "HIV infected dendritic cells impair T cell function : reversal of defects by soluble CD4, but not by antiretroviral drugs"J. Immunol.. (in press). (2003)

[Publications] Yoshimura K., Mitsuya H.et al.: "UIC-64003 : a potent protease inhibitor (PI) that inhibits multi-PI-resistant HIV-1 replication in. vitro"J. Virol.. 76. 1349-1358 (2002)

[Publications] Miyakawa T.Mitsuya, H.et al.: "Identification of amino acid residues critical for LD78β (a variant of human macrophage inflammatory protein-1α) binding to CCRS and inhibition of R54 HIV-1 replication"J. Biol. Chem.. 277. 4649-4655 (2002)

[Publications] Gatanaga H., Mitsuya H.et al.: "Amino acid substitutions in non-cleavage sites of the gag region are indispensable for high level HIV-1 resistance to protease inhibitors"J. Biol. Chem.. 277. 5952-5961 (2002)

満屋裕明熊本大学, 医学部, 教授 (20136724)