Inhibition of HIV-1 Integrase-LEDGF/P75 Interactions

HIV-1 整合酶-LEDGF/P75 相互作用的抑制

• 批准号: 7897668
• 负责人: NOURI NEAMATI
• 金额: $ 20.4万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-23 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897668
• 关键词: Active Sites; Affect; Antiviral Agents; Antiviral resistance; Biological Assay; Biology; Cell Line; Cell physiology; Development; Disease; Drug Delivery Systems; Drug Design; Enzymes; Exhibits; Fluorescence; Genetic; Goals; HIV-1; HIV-1 integrase; Highly Active Antiretroviral Therapy; Integrase; Integrase Inhibitors; Libraries; Life Cycle Stages; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Proteins; RNA-Directed DNA Polymerase; Resistance; Series; Spottings; Staging; Structure; Testing; Therapeutic; Toxic effect; Treatment Protocols; Viral; antiretroviral therapy; base; cofactor; cytotoxicity; design; drug discovery; drug resistant virus; high throughput screening; inhibitor/antagonist; innovation; mutant; novel; programs; protein protein interaction; public health relevance; resistant strain; small molecule; therapeutic target; three dimensional structure; transcriptional coactivator p75; virtual

DESCRIPTION (provided by applicant): Our central hypothesis is that the interaction between HIV-1 integrase (IN) and the cellular co-factor LEDGF/p75 is important for efficient viral replication. We further hypothesize that inhibitors of this interaction have antiviral activity, a low chance of inducing antiviral resistance, and should have low toxicity. Designed drugs targeting an essential IN-cofactor hotspot will have a major impact on current treatment regimens. The IN- LEDGF/p75 disrupting drugs would display synergistic interactions with components of HAART cocktails. Because these designed drugs target spots different from the active site, they would also display synergy with other IN inhibitors presently in development, which target the active site of the enzyme. Patients receiving HAART therapy over long periods often develop drug resistant viral strains. Drugs specific for IN-LEDGF/p75 interactions represent a completely different class of compounds, and target different stages in the viral life cycle. Viral strains exhibiting resistance to reverse transcriptase, protease, or even IN inhibitors would still be susceptible to this class of therapeutics. Additionally, the emergence rate of viral strains resistant to potential IN-LEDGF/p75 disrupting drugs would presumably be considerably slower than that to traditional antiviral therapeutics since the interface includes a cellular protein with much lower genetic variability. The study of IN cofactors and the design of potential IN-cofactor disrupting drugs is an emerging field with the potential for major developments. Previously, we created eukaryotic 293T cell lines stably expressing IN and identified LEDGF/p75 as an important cellular co-factor of IN. Recently, we have developed a high throughput assay to screen for inhibitors of the LEDGF/p75-IN interaction and have identified a series of novel inhibitors. In this proposal our goal is to characterize these inhibitors, especially their interaction with IN, antiviral activity, and design optimized inhibitors selectively blocking their interactions with IN. More specifically we propose: Aim 1. To design novel inhibitors of the LEDGF/p75-IN interaction and Aim 2. To validate our top 10 compounds as bona fide inhibitors of IN-LEDGF/p75 interaction. Successful completion of this study will show that this innovative strategy provides a new target and inhibitor for antiretroviral therapy and for further interrogating the LEDG/p75 pathway. By extension this approach can be exploited in other diseases where protein-protein interactions can be safely inhibited without affecting cellular function. PUBLIC HEALTH RELEVANCE: HIV-1 integrase interacts with a series of cellular co-factors and many of these interactions such as with LEDGF/p75 are important for efficient viral replication. Selective inhibition of these interactions provides a unique strategy to design novel and safe drugs with antiviral activity.

描述（由申请人提供）：我们的中心假设是HIV-1积分酶（IN）与细胞副因素LEDGF/p75之间的相互作用对于有效的病毒复制很重要。我们进一步假设这种相互作用的抑制剂具有抗病毒活性，诱导抗病毒药抗性的可能性很小，并且毒性应低。针对基本的伴侣热点的设计药物将对当前的治疗方案产生重大影响。 IN-LEDGF/P75破坏药物将与Haart鸡尾酒的组成部分显示协同的相互作用。由于这些设计的药物针对的是不同于活性部位的斑点，因此它们还将与目前正在开发的抑制剂中的其他抑制剂表现出协同作用，该抑制剂针对酶的活性部位。长期接受HAART治疗的患者通常会发展出耐药性病毒菌株。特异性的药物对列出的GF/p75相互作用代表了完全不同的化合物，并且在病毒生命周期中靶向不同的阶段。表现出对逆转录酶，蛋白酶甚至抑制剂的抗性的病毒菌株仍然容易受到此类疗法的影响。此外，由于界面包括具有较低遗传变异性的细胞蛋白，因此对潜在的LEDGF/p75破坏药物的抗性病毒菌株的出现率可能比传统的抗病毒治疗剂要慢得多。在辅助因子中的研究以及破坏药物的潜在竞争激素的设计是一个新兴领域，具有重大发展的潜力。以前，我们创建了稳定表达并确定LEDGF/p75的真核293T细胞系，是IN的重要细胞共同因素。最近，我们开发了一种高通量测定法，以筛选LEDGF/P75-IN相互作用的抑制剂，并确定了一系列新型抑制剂。在此提案中，我们的目标是表征这些抑制剂，尤其是它们与IN抗病毒活性的相互作用，并选择性地抑制剂选择性地阻止了它们与IN的相互作用。更具体地说，我们提出：目标1。设计LEDGF/P75-IN相互作用的新型抑制剂和AIM 2。验证我们的前10种化合物作为In-LeDGF/P75相互作用的真正抑制剂。这项研究的成功完成将表明，这种创新策略为抗逆转录病毒疗法提供了新的靶标和抑制剂，并进一步询问LEDG/P75途径。通过扩展，可以在可以安全抑制蛋白质 - 蛋白质相互作用而不会影响细胞功能的其他疾病中利用这种方法。公共卫生相关性：HIV-1积分酶与一系列细胞共同因素相互作用，其中许多相互作用（例如与LEDGF/p75）相互作用对于有效的病毒复制非常重要。选择性抑制这些相互作用为设计具有抗病毒活性的新型和安全药物提供了独特的策略。

项目成果

A symmetric region of the HIV-1 integrase dimerization interface is essential for viral replication.

HIV-1 整合酶二聚化界面的对称区域对于病毒复制至关重要。

• DOI: 10.1371/journal.pone.0045177
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Serrao,Erik;Thys,Wannes;Demeulemeester,Jonas;Al-Mawsawi,LaithQ;Christ,Frauke;Debyser,Zeger;Neamati,Nouri
• 通讯作者: Neamati,Nouri

Design of cell-permeable stapled peptides as HIV-1 integrase inhibitors.

• DOI: 10.1021/jm4006516
• 发表时间: 2013-07-11
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Long YQ;Huang SX;Zawahir Z;Xu ZL;Li H;Sanchez TW;Zhi Y;De Houwer S;Christ F;Debyser Z;Neamati N
• 通讯作者: Neamati N

Fragment-based discovery of 8-hydroxyquinoline inhibitors of the HIV-1 integrase-lens epithelium-derived growth factor/p75 (IN-LEDGF/p75) interaction.

• DOI: 10.1021/jm301632e
• 发表时间: 2013-03-28
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Serrao E;Debnath B;Otake H;Kuang Y;Christ F;Debyser Z;Neamati N
• 通讯作者: Neamati N

Design of HIV-1 integrase inhibitors targeting the catalytic domain as well as its interaction with LEDGF/p75: a scaffold hopping approach using salicylate and catechol groups.

• DOI: 10.1016/j.bmc.2011.06.058
• 发表时间: 2011-08-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Fan, Xing;Zhang, Feng-Hua;Al-Safi, Rasha I.;Zeng, Li-Fan;Shabaik, Yumna;Debnath, Bikash;Sanchez, Tino W.;Odde, Srinivas;Neamati, Nouri;Long, Ya-Qiu
• 通讯作者: Long, Ya-Qiu

Discovery of novel inhibitors of LEDGF/p75-IN protein-protein interactions.

• DOI: 10.1016/j.bmc.2012.12.012
• 发表时间: 2013-02-15
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Sanchez TW;Debnath B;Christ F;Otake H;Debyser Z;Neamati N
• 通讯作者: Neamati N