| Nakata, H., Maeda, K., Miyakawa, T., Shibayama, S., Matsuo, M., Takaoka, Y., Ito, M., Koyanagi, Y., and Mitsuya, H. (2005) Potent anti-R5 human immunodeficiency virus type 1 effects of a CCR5 antagonist, AK602/ONO4128/GW873140, in a novel human peripheral blood mononuclear cell nonobese diabetic-SCID, interleukin-2 receptor g-chain-knocked-out AIDS mouse model. J. Virol. 79: 2087-2096. |
| We established human peripheral blood mononuclear cell (PBMC)-transplanted R5 human immunodeficiency virus type 1 isolate JR-FL (HIV-1JR-FL)-infected, nonobese diabetic-SCID, interleukin 2 receptor-chain-knocked-out (NOG) mice, in which massive and systemic HIV-1 infection occurred. The susceptibilityof the implanted PBMC to the infectivity and cytopathic effect of R5 HIV-1 appeared to stem from hyperactivation of the PBMC, which rapidly proliferated and expressed high levels of CCR5. When a novel spirodiketopiperazine-containing CCR5 inhibitor, AK602/ONO4128/GW873140 (molecular weight, 614), was administeredto the NOG mice 1 day after R5 HIV-1 inoculation, the replication and cytopathic effects of R5 HIV-1 were significantly suppressed. In saline-treated mice (n=7), the mean human CD4/CD8 cell ratio was 0.1 on day 16 after inoculation, while levels in mice (n=8) administered AK602 had a mean value of 0.92, comparable to levels in uninfected mice (n=7). The mean number of HIV-RNA copies in plasma in saline-treated mice were 106/ml on day 16, while levels in AK602-treated mice were 1.27 103/ml (P=0.001). AK602 also significantly suppressed the number of proviral DNA copies and serum p24 levels (P=0.001). These data suggest that the present NOG mouse system should serve as a small-animal AIDS model and warrant that AK602 be further developed as a potential therapeutic for HIV-1 infection. |
| エイズモデルSCIDマウスにR5-HIV-1 (HIV-1JR-FL) を感染させ、24時間後からAK602の投与を開始した。感染後16日の時点でAK602投与群は無治療群に比べ、約2logのHIV-RNA量の抑制が認められた(p=0.001)。また感染後5-16日目におけるHIV-RNA量の増加率についてもAK602投与群と無治療群では有意な差が認められた (p=0.0057)。これらの結果はAK602の有用性を強く示唆するもので臨床試験へと進める根拠として良いと思われる。 |
| Ghosh, A.K., Swanson, L.M., Cho, H., Leshchenko, S., Hussain, K.A., Kay, S., Wlaters, D.E., Koh, Y., and Mitsuya, H. (2005) Structure-Based Design: Synthesis and biological evaluation of a series of novel cycloamide-derived HIV-1 protease inhibitors. J Med Chem 48:3576-3585. |
| The structure-based design and synthesis of a series of novel nonpeptide HIV protease inhibitorsare described. The inhibitors were designed based upon the X-ray crystal structure of inhibitor 1 (UIC-94017)-bound HIV-1 protease. The inhibitors incorporated 3-hydroxysalicyclic acidderived acyclic and cyclic P2 ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. The inhibitors contain only two chiral centers and are readily synthesized in optically active form utilizing Sharpless asymmetric epoxidation, regioselective epoxide opening, and ring-closing olefin metathesis using Grubbs catalyst as the key steps. We have synthesized 13-15-membered cycloamides and evaluated their HIV-1 protease enzyme inhibitory and antiviral activities in MT-2 cells. Interestingly, all cycloamide-derived inhibitors are noticeably more potent than the corresponding acyclic compounds. The ring size and substituent effects were investigated. It turned out that the 14-membered saturated ring is preferred by the S1-S2 active sites of HIV-1 protease. Macrocycle 26 showed excellent enzyme inhibitory potency with a Ki value of 0.7 nM and an antiviral IC50 value of 0.3 M. In view of their structural simplicity and preliminary interesting results, further optimization of these inhibitors is underway. |
| 一連の新規の非ププチド性プロテア?ゼ阻害剤をUIC-94017の結晶構造データに基づいてデザイン、合成した。Cycloamide誘導体は強力な活性を有しており、macrocycle 26はKi 値が 0.7 nMと強い酵素阻止能が得られたが、抗ウイルス活性のIC50値は 0.3 Mであった。これらのプロテアーゼ阻害剤の特性は興味深く、これからの最適化 optimization が望まれる。 |
| Matsushita, S., Yoshimura, K., Kimura, T., Kamihira, A., Takano, M., Etoh, K., Shirasaka, T., Mitsuya, H., and Oka, S. (2005) Spontaneous recovery of hemoglobin and neutrophil levels in japanese patients on a long-term Combivirｨ containing regimen. J. Clin. Virol. 33:188-193. |