Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies
Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies
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DOI：
10.1039/b809178a
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发表时间：
2008-10-21
影响因子：
3.2
通讯作者：
Mitsuya, Hiroaki
中科院分区：
文献类型：
--
作者：
Ghosh, Arun K.;Gennna, Sandra;Mitsuya, Hiroaki
最近，我们设计了一系列新的HIV-1蛋白酶抑制剂，其中含有立体化学定义的双环融合环戊基（Cp-THF）聚氨酯作为高亲和力的p2配体。具有这种p2配体的抑制剂1对多重耐药临床分离株显示出非常令人印象深刻的效力。基于1结合的HIV-1蛋白酶x射线结构，我们现在已经设计和合成了许多中双环配体，它们可以想象与Cp-THF配体类似的相互作用。中位配体的设计很有吸引力，因为它们不含任何立体中心。含有双环-1,3-二恶烷脲烷和双环-1,4-二恶烷脲烷的抑制剂显示出有效的酶抑制和抗病毒活性。抑制剂2 （K-i = 0.11 nM, IC50 = 3.8 nM）在该系列中表现出非常强的抗病毒活性。抑制剂3具有相当的酶抑制活性（K-i = 0.18 nM），但其抗病毒活性（IC50 = 170 nM）明显弱于抑制剂2。抑制剂2对一系列多药耐药临床分离株的抗病毒效力与amprenavir相当。3结合HIV-1蛋白酶的蛋白质配体x射线结构揭示了s2亚位上的一些关键氢键相互作用。基于这种x射线结构，我们创建了抑制剂2的活性模型。
Recently, we designed a series of novel HIV-1 protease inhibitors incorporating a stereochemically defined bicyclic fused cyclopentyl (Cp-THF) urethane as the high affinity P2-ligand. Inhibitor 1 with this P2-ligand has shown very impressive potency against multi-drug-resistant clinical isolates. Based upon the 1-bound HIV-1 protease X-ray structure, we have now designed and synthesized a number of meso-bicyclic ligands which can conceivably interact similarly to the Cp-THF ligand. The design of meso-ligands is quite attractive as they do not contain any stereocenters. Inhibitors incorporating urethanes of bicyclic-1,3-dioxolane and bicyclic-1,4-dioxane have shown potent enzyme inhibitory and antiviral activities. Inhibitor 2 (K-i = 0.11 nM; IC50 = 3.8 nM) displayed very potent antiviral activity in this series. While inhibitor 3 showed comparable enzyme inhibitory activity (K-i = 0.18 nM) its antiviral activity (IC50 = 170 nM) was significantly weaker than inhibitor 2. Inhibitor 2 maintained an antiviral potency against a series of multi-drug resistant clinical isolates comparable to amprenavir. A protein-ligand X-ray structure of 3-bound HIV-1 protease revealed a number of key hydrogen bonding interactions at the S2-subsite. We have created an active model of inhibitor 2 based upon this X-ray structure.