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标题：In Vitro and Ex Vivo Anti-human Immunodeficiency Virus (HIV) Activities of a New Water-Soluble HIV Protease Inhibitor, R-87366, Containing (2S, 3S)-3-Amino-2-hydroxy-4-phenylbutanoic Acid
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作者：Tomoaki KOMAI ; Ryuichi YAGI ; Hisayo SUZUKI-SUNAGAWA 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1997
卷号：20
期号：2
页码：175-180
DOI：10.1248/bpb.20.175
出版社：The Pharmaceutical Society of Japan
摘要：In a series of compounds containing (2S, 3S)-3-amino-2-hydroxy-4-phenylbutanoic acid (AHPBA), a transition-state mimetic, R-87366 : (2S, 3S)-3-[N-(quinoxaline-2-carbonyl)-L-asparaginyl]amino-2-hydroxy-4-phenylbutanoyl-L-proline tert-butylamide, was found to be a potent human immunodeficiency virus protease inhibitor (K_i value was 11 nM) and anti-HIV agent (IC₉₀ value was 0.5 μM for HIV-1IIIB acutely infected cells) with moderate water-solubility (4.2 mg/ml at 25°C). The compound was also active in chronically infected Molt-4/HIV-1IIIB cells, and inhibited the proteolytic processing of p55 into p17, suggesting that its anti-HIV activity was derived from HIV protease inhibition.The compound showed more potent activity (IC₉₀ value was 0.03-0.25 μM) against clinial isolates of HIV in 5 out of 6 patients examined with varying clinical status in an ex vivo assay. One isolate, however, from the sixth patient, was less sensitive to R-87366 (IC₉₀ value was 0.5 μM). In experiments with this strain, R-87366 showed comparatively low efficacy in acutely infected peripheral blood mononuclear cell (PBMC). This result suggests that the diversity of sensitivity shown in the ex vivo assay could be caused by the viral property itself. As a result of the determination of nucleic acid sequences in the clinical isolates, some amino acids were found to be substituted in the protease region, in contrast to the HIV-1 clade B consensus sequence, and some of them have been reported to contribute to the susceptibility of HIV protease inhibitors.
关键词：AIDS;HIV-1 protease inhibitor;3-amino-2-hydroxy-4-phenylbutanoic acid;ex vivo assay