HIV capsid is a tractable target for small molecule therapeutic intervention.
HIV capsid is a tractable target for small molecule therapeutic intervention.
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DOI：
10.1371/journal.ppat.1001220
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发表时间：
2010-12-09
期刊：
影响因子：
6.7
通讯作者：
Butler SL
中科院分区：
文献类型：
--
作者：
Blair WS;Pickford C;Irving SL;Brown DG;Anderson M;Bazin R;Cao J;Ciaramella G;Isaacson J;Jackson L;Hunt R;Kjerrstrom A;Nieman JA;Patick AK;Perros M;Scott AD;Whitby K;Wu H;Butler SL
尽管目前艾滋病毒抗逆转录病毒治疗的护理标准很高，但多药耐药菌株仍在不断出现，这突出表明需要额外的新机制抑制剂，以提供临床上更多的治疗选择。我们报告了一类新的小分子抗逆转录病毒化合物，通过一种新的作用机制直接靶向HIV-1衣壳（CA）。这些化合物对HIV-1实验室菌株、临床分离株和HIV-2表现出有效的抗病毒活性，并抑制病毒复制周期中的早期和晚期事件。我们目前的机制研究表明，这些早期和晚期活动的化合物影响病毒的脱壳和组装，分别。我们表明，HIV-1 CA的N-末端结构域中的氨基酸取代足以赋予对这类化合物的抗性，从而将CA鉴定为受感染细胞中的靶标。与HIV-1 CA结合的化合物的高分辨率共晶体结构揭示了蛋白质N-末端结构域中的新结合口袋。我们的数据表明，广谱的抗病毒活性可以通过靶向这个新的结合位点，并揭示艾滋病毒CA作为一个易于处理的药物靶点的艾滋病毒治疗。虽然目前对人类免疫缺陷病毒（HIV）的护理标准很高，但病毒对目前临床上的每种药物都产生了耐药性，在某些情况下使整个类别对患者无效。一种新的抗逆转录病毒药物将有效地对抗对任何现有药物都有抗药性的HIV-1菌株，并将扩大患者的治疗选择。衣壳是HIV的主要结构蛋白，并且是病毒复制周期的关键部分，无论是在病毒颗粒的组装还是在宿主细胞的感染中。我们报告了一类新的抗逆转录病毒药物，靶向HIV-1衣壳，并证明它是活跃在病毒复制周期的两个关键阶段。这些化合物对各种亚型的一系列HIV-1临床毒株以及HIV-2始终有效。最后，化合物结合在衣壳上的独特口袋中，该口袋先前未被强调为药物结合位点。我们相信这类新的抗逆转录病毒药物可以作为开发新一代HIV-1治疗药物的起点，更普遍地说，强调了衣壳作为治疗靶点的潜力。
Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy. Although the current standard of care for Human Immunodeficiency Virus (HIV) is high, viral resistance has emerged to every drug currently in the clinic, in some cases rendering the entire class ineffective for patients. A new class of antiretroviral drugs would be effective against strains of HIV-1 that are resistant to any existing drug and would expand the therapeutic options available to patients. Capsid is the primary structural protein of HIV and a critical part of the viral replication cycle, both in the assembly of viral particles and in the infection of host cells. We report a new class of antiretrovirals that targets HIV-1 capsid and demonstrate that it is active at two critical stages in the viral replication cycle. These compounds were consistently effective against a range of clinical strains of HIV-1, from various sub-types, as well as HIV-2. Finally, the compounds bind in a unique pocket on capsid that has not previously been highlighted as a drug binding site. We believe this new class of antiretrovirals can serve as a starting point for the development of a new generation of HIV-1 therapeutics and, more generally, underscores the potential of capsid as a therapeutic target.
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影响因子：
4.9
作者：
Cao, J;Isaacson, J;Blair, WS
通讯作者：
Blair, WS
影响因子：
5.4
作者：
Lanman, J;Sexton, J;Prevelige, PE
通讯作者：
Prevelige, PE
影响因子：
5.4
作者：
Ako-Adjei, D;Johnson, MC;Vogt, VM
通讯作者：
Vogt, VM
影响因子：
5.4
作者：
Ganser-Pornillos, BK;von Schwedler, UK;Sundquist, WI
通讯作者：
Sundquist, WI
DOI：
10.1107/s0907444994003112
发表时间：
1994-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
BAILEY, S
通讯作者：
BAILEY, S