Potent inhibition of HIV-1 latency reversal by PF 03758309

PF 03758309 有效抑制 HIV-1 潜伏期逆转

基本信息

批准号：
10409846
负责人：
NICOLAS PAUL SLUIS-CREMER
金额：
$ 18.89万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-24 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409846
关键词：
ATF2 gene Animal Model Biological Assay CD4 Positive T Lymphocytes CREB1 gene Cell model Cells Clinical Data Dose Down-Regulation Event Gene Silencing Genetic Transcription Goals HIV HIV-1 Histones Individual Infection JUN gene Laboratories Lead MAPK Signaling Pathway Pathway Maintenance Nucleosomes Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Phenotype Proteomics Proviruses Research Rest Safety Shock Signal Pathway Signal Transduction Solid Neoplasm Viral Viral reservoir Virus antiretroviral therapy cellular targeting chromatin immunoprecipitation chromatin remodeling drug development indexing inhibitor innovative technologies insight kinase inhibitor liquid chromatography mass spectrometry new therapeutic target novel organizational structure p21 activated kinase prevent reactivation from latency response small molecule inhibitor transcription factor viral rebound

项目摘要

SUMMARY The persistence of latent, replication-competent HIV-1 proviruses in resting CD4+ T cells represents a major barrier to curing HIV-1 infection. To date, efforts to eradicate this viral reservoir via the shock and kill approach have not led to complete, long term viral suppression in either cell and/or animal models. Thus, we need to consider alternate approaches that could lead to a sterilizing or functional cure for HIV-1 infection. The block and lock approach seeks to silence the transcriptional activity of latent proviruses, such that when antiretroviral therapy (ART) is removed viral rebound is significantly delayed or, better yet, prevented. Several research groups have identified small molecule inhibitors that target different factors of the HIV-1 transcription machinery, leading to a block and lock phenotype. However, blocking only one transcription pathway may not be sufficient to silence all proviruses, and thus it is likely that successful implementation of this strategy will require a combination of inhibitors. In this regard, there is a critical need to identify new molecules with different mechanisms of action. Our laboratory recently discovered that the p21-activated kinase (PAK) inhibitor PF- 03758309 is an exceptionally potent inhibitor of HIV-1 latency reactivation (IC50 in the pM to low nM range) with a huge selectivity index (> 3,000). (The discovery of PF-03758309 as an inhibitor of HIV-1 latency reversal is described in: Vargas B, Giacobbi NS, Sanyal A, Venkatachari NJ, Han F, Gupta P, Sluis-Cremer N. Antimicrob Agents Chemother. Inhibitors of Signaling Pathways That Block Reversal of HIV-1 Latency. 2019 Jan 29;63(2). pii: e01744-18.) In the long term, we anticipate that PF-03758309 alone, or in combination with other drugs, could be used to facilitate a “block and lock” sterilizing cure in HIV-infected individuals. However, we do not know the mechanism(s) by which this inhibitor abrogates the reactivation of latent HIV-1 infection in CD4+ T cells. Indeed, preliminary studies in our laboratory revealed that its inhibition of HIV-1 latency reversal is not due to inhibition of the PAKs. Accordingly, the primary goal of this R21 proposal is to elucidate the mechanism(s) by which PF-03758309 silences HIV-1 proviruses.

概括在静止CD4+ T细胞中，潜在的，具有复制能力的HIV-1病毒的持久性代表了一个主要治愈HIV-1感染的障碍。迄今为止，努力通过冲击和杀戮方法来消除这种病毒储层在细胞和/或动物模型中尚未导致长期的长期病毒抑制。那我们需要考虑可能导致HIV-1感染的替代方法，以便治疗HIV-1。块锁定方法试图使潜在病毒的转录活性保持沉默，以便在抗逆转录病毒时去除治疗（ART）的病毒反弹被显着延迟或更好地阻止。几项研究组已经鉴定出针对HIV-1转录不同因子的小分子抑制剂机械，导致块并锁定表型。但是，仅阻止一个转录途径可能不会足以使所有规定都沉默，因此，成功实施该策略很可能会需要组合抑制剂。在这方面，识别不同的新分子有不同的需求作用机理。我们的实验室最近发现P21激活激酶（PAK）抑制剂PF- 03758309是HIV-1潜伏期重新激活（PM中的IC50至低NM范围的IC50）的特殊潜在抑制剂巨大的选择性指数（> 3,000）。（发现PF-03758309作为HIV-1潜伏期抑制剂的发现是描述了：Vargas B，Giacobbi NS，Sanyal A，Venkatachari NJ，Han F，Gupta P，Sluis-Cremer N. 抗菌剂化学剂。信号通路的抑制剂阻断了HIV-1潜伏期的逆转。 2019 1月29日; 63（2）。 PII：E01744-18。）从长远来看，我们预计仅PF-03758309或与其他药物可用于促进艾滋病毒感染者中的“阻塞和锁定”治疗。然而，我们不知道该抑制剂废除潜在HIV-1感染的重新激活的机制 CD4+ T细胞。确实，我们实验室的初步研究表明，其抑制HIV-1潜伏期逆转不是由于抑制PAK。根据该R21提案的主要目标是阐明 PF-03758309 Silences HIV-1 Proviruse的机制。