Inhibitors of HIV-induced downregulation of HLA class I

HIV 诱导的 I 类 HLA 下调的抑制剂

基本信息

批准号：
8465183
负责人：
JUAN LAMA
金额：
$ 21.02万
依托单位：
RETROVIROX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8465183
关键词：
Acquired Immunodeficiency Syndrome Adenoviruses Adverse effects Animal Model Anti-Retroviral Agents Antigen Presentation Antiviral Agents Biological Assay Biological Availability CD8B1 gene Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Chemicals Cytomegalovirus DNA Sequence Rearrangement Data Analyses Development Down-Regulation Drug resistance Family Flow Cytometry Foundations Frequencies Future Goals HIV HIV Infections Herpesviridae Herpesvirus 1 Highly Active Antiretroviral Therapy Housing Human Human Herpesvirus 2 Immune Immune response In Vitro Infection Knowledge Lead Libraries MHC Class I Genes Macaca Membrane Proteins Morphologic artifacts Multi-Drug Resistance Natural Killer Cells Oral Papillomavirus Pathogenesis Patients Persons Pharmaceutical Chemistry Pharmaceutical Preparations Phase Phosphotransferases Play Poxviridae Preclinical Drug Evaluation Principal Investigator Procedures Property Proteins Regulation Research Resistance Risk Role SIV Scientist Specificity Staging Structure Surface Testing Therapeutic Index Time Toxic effect Triage United States Validation Vendor Viral Antigens Viral Pathogenesis Viral Proteins Virus Virus Replication Work base cell killing combat cytotoxicity drug development drug discovery drug resistant virus experience immune function improved in vitro activity in vitro testing in vivo inhibitor/antagonist killings lead series nef Protein novel operation phase 1 study pre-clinical programs receptor resistant strain response scaffold screening small molecule small molecule libraries src-Family Kinases success

项目摘要

DESCRIPTION (provided by applicant): Inhibitors of HIV-induced downregulation of HLA class I Multiple studies suggest that downmodulation of HLA class I (MHC-I) plays an important role in HIV infection. The viral protein Nef induces MHC-I downmodulation and interferes with the presentation of viral antigens, making HIV-infected cells less sensitive to killing by CD8-positive CTLs. Macaques infected with SIV deficient in this activity rapidly restore the ability to eliminate MHC-I. The mechanism by which Nef downmodulates MHC-I has been extensively investigated, however, despite its important role in pathogenesis this activity remains to be targeted for antiviral development. Further highlighting the importance of this function in immune evasion, interference with antigen presentation has also been recognized in many herpesviruses, poxviruses, papillomaviruses and adenoviruses. We propose screening a library of small molecules to identify inhibitors of the HIV-induced MHC-I downmodulation. A high content screen has been fully optimized and preliminary findings from a test pilot of 3,440 small-molecules have validated the assay and identified small-molecules blocking this promising target. Our results demonstrate proof-of-concept that potent and specific interference of MHC-I downmodulation with small molecules is possible. We propose the following aims: (1) to screen a library of 46,280 drug-like molecules composed of highly diverse structures, including molecules selected to target kinases, and other compounds known to be pharmacologically active (Lopac library); (2) to validate and characterize the potency, specificity and toxicity of hts, and; (3) to identify compounds that enhance the ability of CTLs to kill HIV- infected cells. We wil use a multi-modal HTS assay with multiple built-in controls to simultaneously confirm hits in primary screens and eliminate false positives with poor toxicity profiles, and other hits blocking HIV infection by known mechanisms. Success in this Phase I application will be defined by identifying one or more bona fide lead series of drug-like compounds with EC50s below 5¿M, minimal cytotoxicity (CC50 at least 30-fold greater than EC50), and the ability to sensitize HIV-infected cells to CTL killing. In a Phase II proposal, chemical leads from this screen will be selected for medicinal chemistry SAR optimization for potency, specificity and oral bioavailability. We wil further study the mechanism of action, characterize drug-resistant strains, ases the potential for antagonism with approved antiretrovirals, and evaluate cross-resistance with other drugs. Additionally, a selected number of compounds will be tested in a small-animal model of HIV infection that recapitulates the virus-specific CTL responses. Compounds with improved profiles and characterized mechanism of action will be advanced into preclinical development studies to support future human trials. Administration of antivirals inhibiting MHC-I downmodulation may lengthen the time required before initiation of HAART therapy, or alternatively, in combination with other drugs may enhance their antiviral effect by improving the patient's immune response against the virus. These studies will constitute the foundation of a drug discovery program that may lead to first-in-class drugs of a novel family of antivirals with the potential for broader activity against other viruses. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

描述（由申请人提供）：HIV 诱导的 I 类 HLA 下调的抑制剂多项研究表明，I 类 HLA (MHC-I) 的下调在 HIV 感染中发挥重要作用。病毒蛋白 Nef 诱导 MHC-I 下调并干扰。随着病毒抗原的呈递，使 HIV 感染的细胞对缺乏这种活性的 SIV 感染的 CD8 阳性 CTL 的杀伤不太敏感，从而迅速恢复杀伤能力。 Nef 下调 MHC-I 的机制已被广泛研究，然而，尽管其在发病机制中发挥重要作用，但该活性仍有待进一步强调该功能在免疫逃避、干扰中的重要性。在许多疱疹病毒、痘病毒、乳头瘤病毒和腺病毒中也发现了抗原呈递，我们建议筛选小分子文库来鉴定 HIV 诱导的 MHC-I 下调的抑制剂。内容筛选已得到全面优化，3,440 个小分子的试验初步结果验证了该检测方法并确定了阻断这一有希望的靶点的小分子，我们的结果证明了 MHC-I 下调的有效且特异性的干扰。我们提出以下目标：（1）筛选由高度多样化结构组成的 46,280 个类药分子库，包括选择用于靶向激酶的分子以及已知具有药理活性的其他化合物。（Lopac 库）；（2）验证和表征 hts 的效力、特异性和毒性；（3）鉴定增强 CTL 杀死 HIV 感染细胞的能力的化合物。具有多个内置对照的检测可同时确认初级筛选中的命中并消除毒性较差的假阳性，以及通过已知机制阻止 HIV 感染的其他命中将通过识别一个或多个真正的先导来定义。类似毒品系列EC50 低于 5¿ 的化合物M，最小的细胞毒性（CC50 至少比 EC50 大 30 倍），以及使 HIV 感染的细胞对 CTL 杀伤敏感的能力。在 II 期提案中，将从该筛选中选择化学先导物进行药物化学 SAR 优化，以提高效力。、特异性和口服生物利用度，我们将进一步研究作用机制，表征耐药菌株，确定与已批准的抗逆转录病毒药物的拮抗潜力，并评估与其他药物的交叉耐药性。此外，还将在 HIV 感染的小动物模型中测试一些选定的化合物，以重现具有改善特征的病毒特异性 CTL 反应。特征性的作用机制将进入临床前开发研究，以支持未来的人体试验，施用抑制 MHC-I 下调的抗病毒药物可能会延长开始 HAART 治疗之前所需的时间，或者，与其他药物联合使用可以通过改善患者对病毒的免疫反应来增强其抗病毒效果。这些研究将构成药物发现计划的基础，该计划可能会产生新型抗病毒药物家族的一流药物。具有针对其他病毒更广泛的活性的潜力 PHS 398/2590（修订版 06/09）页继续格式页