Suppression of HIV-1 protease inhibitor resistance by phosphonate-mediated solvent anchoring
Suppression of HIV-1 protease inhibitor resistance by phosphonate-mediated solvent anchoring
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DOI：
10.1016/j.jmb.2006.07.073
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发表时间：
2006-10-27
影响因子：
5.6
通讯作者：
Lee, William A.
中科院分区：
文献类型：
--
作者：
Cihlar, Tomas;He, Gong-Xin;Lee, William A.
人类免疫缺陷病毒1型（HIV-1）蛋白酶抑制剂（PI）的引入显著改善了HIV-1感染的临床结局和控制。然而，由于病毒蛋白酶的广泛突变，PI之间的交叉耐药性是限制其更广泛临床应用的主要因素。在这里，我们报告使用共价连接的膦酸基序的肽模拟物抑制剂支架的PI电阻的抑制。所得膦酸酯类似物保持对HIV-1蛋白酶的高结合亲和力、有效的抗逆转录病毒活性，并且与母体分子不同，其对一组临床上重要的PI抗性HIV-1菌株的效力没有损失。如晶体学分析所示，膦酸酯部分高度暴露于溶剂，与任何酶活性位点或表面残基没有可辨别的相互作用。我们将这种效应称为“溶剂锚定”，并证明它是由与突变酶相互作用后抑制剂结合熵的有利变化驱动的。这种类型的热力学行为，这是没有发现与母支架完全埋在酶活性位点，是一个结果的抑制剂结合状态的简并性增加，允许有效的分子适应突变蛋白酶的扩大腔体积。这种策略适用于各种PI支架，应该有助于设计新的PI和潜在的其他抗病毒治疗药物。(c)2006爱思唯尔有限公司保留所有权利。
The introduction of human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) markedly improved the clinical outcome and control of HIV-1 infection. However, cross-resistance among PIs due to a wide spectrum of mutations in viral protease is a major factor limiting their broader clinical use. Here we report on the suppression of PI resistance using a covalent attachment of a phosphonic acid motif to a peptidomimetic inhibitor scaffold. The resulting phosphonate analogs maintain high binding affinity to HIV-1 protease, potent antiretroviral activity, and unlike the parent molecules, display no loss of potency against a panel of clinically important PI-resistant HIV-1 strains. As shown by crystallographic analysis, the phosphonate moiety is highly exposed to solvent with no discernable interactions with any of the enzyme active site or surface residues. We term this effect "solvent anchoring" and demonstrate that it is driven by a favorable change in the inhibitor binding entropy upon the interaction with mutant enzymes. This type of thermodynamic behavior, which was not found with the parent scaffold fully buried in the enzyme active site, is a result of the increased degeneracy of inhibitor binding states, allowing effective molecular adaptation to the expanded cavity volume of mutant proteases. This strategy, which is applicable to various PI scaffolds, should facilitate the design of novel PIs and potentially other antiviral therapeutics. (c) 2006 Elsevier Ltd. All rights reserved.