Identification of a small-molecule inhibitor of HIV-1 assembly that targets the phosphatidylinositol (4,5)-bisphosphate binding site of the HIV-1 matrix protein.
Identification of a small-molecule inhibitor of HIV-1 assembly that targets the phosphatidylinositol (4,5)-bisphosphate binding site of the HIV-1 matrix protein.
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DOI：
10.1002/cmdc.201200577
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发表时间：
2013-03
期刊：
影响因子：
3.4
通讯作者：
Cocklin S
中科院分区：
文献类型：
--
作者：
Zentner I;Sierra LJ;Fraser AK;Maciunas L;Mankowski MK;Vinnik A;Fedichev P;Ptak RG;Martín-García J;Cocklin S
耐药性的发展仍然是当前HIV-1抗病毒治疗的一个关键问题，因此需要新的HIV-1复制抑制剂。我们之前报道了一种新的抗HIV-1化合物，N2-(phenoxyacetyl)- n -[4-（1-piperidinyl-羰基）苄基]甘氨酸酰胺（14），它与HIV-1基质（MA）蛋白的高度保守的磷脂酰肌醇(4,5)-二磷酸（PI(4,5)P2）结合袋结合。在这项研究中，我们重新评估了用于鉴定化合物14的虚拟屏幕的命中值，并使用原代人外周血单个核细胞直接在HIV-1复制试验中进行了测试。本研究鉴定出3个具有抗病毒活性的新化合物；2-(4-{[3-（4-氟苯基）-1,2,4-恶二唑-5-基]甲基})-1-哌嗪基)-N-(4-（4-硝基苯基）哌嗪-1-基]甲基]-1,2,4-恶二唑（17）和N-[4-乙氧基-3-（1-哌啶基磺基）苯基]-2-（咪唑[2,1-b][1,3]噻唑-6-基）乙酰胺（18），其中化合物7是这些化合物中最有效的。对7的机制研究表明，它直接与HIV-1 MA相互作用并通过其发挥作用。根据我们的药物靶点，化合物7与PI(4,5)P2竞争MA结合，从而减少新病毒的产生。MA的PI(4,5)P2结合位点的残基突变降低了化合物7的抗病毒作用。此外，化合物7表现出广泛中和的抗hiv活性，对M组分离物的IC50值为7.5 ~ 15.6 μm。综上所述，这些结果指向了一种新的化学探针，可以用于更密切地研究MA的生物学作用，并且可以通过进一步优化，导致一类新的抗hiv -1治疗方法。PIP2-ing HIV-1到岗！描述了一种新的靶向HIV-1基质（MA）蛋白的HIV-1复制小分子抑制剂的发现和表征。这种新型药物具有广泛的治疗作用，可以抑制所有被测试的M组分离物，并通过破坏关键的磷脂酰肌醇4,5-二磷酸(PI[4,5]P2)-MA相互作用的新机制起作用。
The development of drug resistance remains a critical problem for current HIV-1 antiviral therapies, creating a need for new inhibitors of HIV-1 replication. We previously reported on a novel anti-HIV-1 compound, N2-(phenoxyacetyl)-N-[4-(1-piperidinyl-carbonyl)benzyl]glycinamide (14), that binds to the highly conserved phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2)binding pocket of the HIV-1 matrix (MA) protein. In this study, we re-evaluate the hits from the virtual screen used to identify compound 14 and test them directly in an HIV-1 replication assay using primary human peripheral blood mononuclear cells. This study resulted in the identification of three new compounds with antiviral activity; 2-(4-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl})-1-piperazinyl)-N-(4-methylphenyl)-acetamide (7), 3-(2-ethoxyphenyl)-5-[[4-(4-nitrophenyl)piperazin-1-yl]methyl]-1,2,4-oxadiazole (17), and N-[4-ethoxy-3-(1-piperidinylsulfonyl)phenyl]-2-(imidazo[2,1-b][1,3]thiazol-6-yl)acetamide (18), with compound 7 being the most potent of these hits. Mechanistic studies on 7 demonstrated that it directly interacts with and functions through HIV-1 MA. In accordance with our drug target, compound 7 competes with PI(4,5)P2 for MA binding and, as a result, diminishes the production of new virus. Mutation of residues within the PI(4,5)P2 binding site of MA decreased the antiviral effect of compound 7. Additionally, compound 7 displays a broadly neutralizing anti-HIV activity, with IC50 values of 7.5–15.6 μm for the group M isolates tested. Taken together, these results point towards a novel chemical probe that can be used to more closely study the biological role of MA and could, through further optimization, lead to a new class of anti-HIV-1 therapeutics. PIP2-ing HIV-1 to the post! The discovery and characterization of a new small-molecule inhibitor (shown) of HIV-1 replication that targets the HIV-1 matrix (MA) protein is described. This novel agent exhibits a broad therapeutic spectrum, inhibiting all of the group M isolates tested, and functions via the novel mechanism of disrupting the critical phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2)-MA interaction.
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影响因子：
4.9
作者：
Parry, Chris M.;Kolli, Madhavi;Pillay, Deenan
通讯作者：
Pillay, Deenan
DOI：
10.1073/pnas.86.15.5781
发表时间：
1989-08-01
影响因子：
11.1
作者：
GOTTLINGER, HG;SODROSKI, JG;HASELTINE, WA
通讯作者：
HASELTINE, WA
影响因子：
5.4
作者：
Ono, A;Freed, EO
通讯作者：
Freed, EO
DOI：
10.1073/pnas.0602941103
发表时间：
2006-10-03
影响因子：
11.1
作者：
Lopez-Verges, Sandra;Camus, Gregory;Berlioz-Torrent, Clarisse
通讯作者：
Berlioz-Torrent, Clarisse
影响因子：
5.4
作者：
Hermida-Matsumoto, L;Resh, MD
通讯作者：
Resh, MD