Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids [electronic resource] : Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies

• Ngôn ngữ: eng
• Ký hiệu phân loại: 630.9 Agriculture and related technologies
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2019
• Mô tả vật lý: Size: p. 1863-1872 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 259962
• Chủ đề: 1. 60 applied life sciences; 2. Brain penetration; 3. Drug resistance; 4. Genetic barriers; 5. Hiv-1 protease inhibitors; 6. Structure-based design

Tóm tắt

 We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. Inhibitors bearing <
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 -THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2' ligands, showed very potent HIV-1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide-derived inhibitors which showed good antiviral IC<
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  value. Boronic acid derived inhibitor with <
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 -THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2-<
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 -THF ligand also showed potent enzyme <
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  but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug-resistant HIV-1 variants. One of the inhibitors maintained good antiviral activity against HIV<
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  and HIV<
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  viruses. We have determined high resolution X-ray structures of two synthetic inhibitors bound to HIV-1 protease and obtained molecular insight into the ligand-binding site interactions.