Design of the anti-HIV protease inhibitor darunavir
Design of the anti-HIV protease inhibitor darunavir
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DOI：
10.1016/b978-0-12-397176-0.00013-3
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发表时间：
2013-01-01
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影响因子：
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通讯作者：
Chapsal, Bruno D.
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文献类型：
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作者：
Ghosh, Arun K.;Chapsal, Bruno D.
HIV蛋白酶抑制剂（PI）的开发及其在高效抗逆转录病毒疗法（HAART）中的应用标志着人类免疫缺陷病毒（HIV）/获得性免疫缺陷综合征（AIDS）治疗突破的开始。HAART治疗方案可以将HIV病毒载量降低到无法检测的水平。然而，艾滋病毒抗药性的迅速出现继续严重损害艾滋病毒感染者的长期治疗选择。我们的基于结构的设计策略，开发PI，专门针对酶的骨架原子，导致了一些非常有效的抑制剂与上级耐药谱。特别值得注意的是，我们开发的立体化学定义的双（四氢呋喃基）氨基甲酸酯作为一个高亲和力的P2配体，导致非常有效的抑制剂的发展。这些抑制剂之一，地瑞那韦，已显示出对HIV-1病毒的特殊效力和对多PI耐药病毒株的上级活性。我们的骨架结合策略得到了证实，详细的晶体结构分析的达芦那韦结合蛋白酶复合物，揭示了一系列保守的抑制剂和HIV-1蛋白酶的关键骨架原子之间的相互作用。达芦那韦于2006年首次获得美国食品和药物管理局（FDA）的加速批准，用于治疗经验丰富、治疗选择很少的患者。它现在已成为对抗艾滋病毒感染和耐药性的领先PI。
The development of HIV protease inhibitors (PIs) and their inclusion in highly active antiretroviral therapies (HAARTs) marked the beginning of a treatment breakthrough in the management of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). The HAART treatment regimen can cut HIV viral load to undetectable levels. Nonetheless, the rapid emergence of HIV drug resistance has continued to seriously compromise long-term treatment options for HIV-infected patients. Our structure-based design strategy to develop PIs that specifically target the enzyme's backbone atoms has resulted in a number of very potent inhibitors with superior drug resistance profiles. Of particular note, our development of stereochemically defined bis(tetrahydrofuranyl) urethane as a high-affinity P2 ligand has led to the development of exceedingly potent inhibitors. One of these inhibitors, darunavir, has shown exceptional potency against the HIV-1 virus and superior activity against multi-PI-resistant viral strains. Our backbone binding strategy was corroborated with detailed crystal structure analyses of darunavir-bound protease complexes which revealed a series of conserved interactions between the inhibitor and key backbone atoms of HIV-1 protease. Darunavir first received accelerated US Food and Drug Administration approval in 2006 for highly treatment-experienced patients with little therapeutic options. It has now become a leading PI in the fight against HIV infection and drug resistance.