Combination of Non-natural D-Amino Acid Derivatives and Allophenylnorstatine−Dimethylthioproline Scaffold in HIV Protease Inhibitors Have High Efficacy in Mutant HIV

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• 作者：Shingo Nakatani ; Koushi Hidaka ; Ei’ ; ichi Ami ; Koichiro Nakahara ; Akihiko Sato ; Jeffrey-Tri Nguyen ; Yoshio Hamada ; Yasuko Hori ; Nobuyuki Ohnishi ; Akinori Nagai ; Tooru Kimura ; Yoshio Hayashi ; Yoshi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：May 22, 2008
• 年：2008
• 卷：51
• 期：10
• 页码：2992 - 3004
• 全文大小：605K
• 年卷期：v.51,no.10(May 22, 2008)
• ISSN：1520-4804

文摘

Several non-natural D-amino acid derivatives were introduced as P₂/P₃ residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease enzyme and HIV-1 replication in MT-4 cells. Structure–activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of α₁-acid glycoprotein in the test medium.