Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies.
Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies.
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DOI：
10.1021/acs.jmedchem.5b00900
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发表时间：
2015-09-10
影响因子：
7.3
通讯作者：
Mitsuya H
中科院分区：
文献类型：
--
作者：
Ghosh AK;Martyr CD;Osswald HL;Sheri VR;Kassekert LA;Chen S;Agniswamy J;Wang YF;Hayashi H;Aoki M;Weber IT;Mitsuya H
基于结构的设计，合成和生物学评价的一系列非常有效的HIV-1蛋白酶抑制剂的描述。为了改善骨架配体-结合位点的相互作用，我们在双四氢呋喃（bis-THF）环的C4位引入了碱性胺。我们推测这些取代基可能在HIV-1蛋白酶的侧翼区产生氢键作用。非对映选择性地进行这些抑制剂的合成。许多抑制剂显示出非常强的酶抑制和抗病毒活性。抑制剂25 f、25 i和25 j针对许多高PI抗性HIV-1毒株进行了评价，它们表现出比地瑞那韦更好的抗病毒活性。25 f和25 g结合的HIV-1蛋白酶的两个高分辨率X射线结构揭示了与Gly 48的主链羰基以及与Gly 48的主链NH在酶活性位点的瓣区中的独特氢键相互作用。这些配体结合位点的相互作用可能是其有效活性的原因。
Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 protease inhibitors are described. In an effort to improve backbone ligand-binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains and they exhibited improved antiviral activity over darunavir. Two high resolution X-ray structures of 25f and 25g-bound HIV-1 protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the flap region of the enzyme active site. These ligand-binding site interactions are possibly responsible for their potent activity.