Inhibitors of HIV-induced downregulation of HLA class I

HIV 诱导的 I 类 HLA 下调的抑制剂

• 批准号: 8410864
• 负责人: JUAN LAMA
• 金额: $ 30万
• 依托单位: RETROVIROX, INC.
• 依托单位国家: 美国
• 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/8410864
• 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; Screening procedure; 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; small molecule; small molecule libraries; src-Family Kinases; success

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 PUBLIC HEALTH RELEVANCE: As of the end of 2010, 34 million people worldwide are estimated to be infected with HIV, and more than 1.8 million deaths occur annually worldwide (UNAIDS estimates). 18,000 persons with AIDS die each year in the United States, approximately 1.2 million people are infected, and this number is steadily growing at a rate of 56,000 new infections every year (CDC estimates). Despite important advances in ARV therapies and more than 30 medications available as single drugs or combinations, side-effects and the emergence or multi-drug resistant viruses still pose important challenges for the treatment of HIV. We propose to identify and characterize antiretroviral compounds that block HIV through a novel mechanism. These unique compounds could be used for the treatment of HIV infection. . 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 感染中发挥着重要作用。病毒蛋白 Nef 诱导 MHC-I 下调并干扰病毒抗原的呈递，使 HIV 感染的细胞对 CD8 阳性 CTL 的杀伤不太敏感。感染了 SIV 且缺乏这种活性的猕猴会迅速恢复能力 消除MHC-I。 Nef 下调 MHC-I 的机制已被广泛研究，然而，尽管它在发病机制中发挥重要作用，但这种活性仍然是抗病毒开发的目标。进一步强调了这一功能在免疫逃避中的重要性，在许多疱疹病毒、痘病毒、乳头瘤病毒和腺病毒中也认识到对抗原呈递的干扰。我们建议筛选一个小分子库来鉴定 HIV 诱导的 MHC-I 下调的抑制剂。高内涵筛选已得到全面优化，3,440 个小分子试验的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。我们的结果证明了小分子对 MHC-I 下调的有效且特异性干扰是可能的。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感染细胞能力的化合物。我们将使用具有多个内置对照的多模式 HTS 测定来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。该一期应用的成功将通过鉴定一种或多种真正的先导系列药物化合物来定义，这些化合物的 EC50 低于 5 µM、最小的细胞毒性（CC50 至少比 EC50 大 30 倍）以及使 HIV 感染细胞对 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，以实现效力、特异性和口服生物利用度。我们将进一步研究作用机制，鉴定耐药菌株， 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，选定数量的化合物将在 HIV 感染的小动物模型中进行测试，该模型重现了病毒特异性 CTL 反应。具有改进特性和特征性作用机制的化合物将进入临床前开发研究，以支持未来的人体试验。给予抑制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能会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，并具有针对其他病毒的更广泛活性的潜力。 PHS 398/2590（修订版 06/09） 页面延续 格式页面 公共卫生相关性：截至 2010 年底，全球估计有 3400 万人感染艾滋病毒，全球每年有超过 180 万人死亡（联合国艾滋病规划署估计）。在美国，每年有 18,000 名艾滋病患者死亡，大约有 120 万人被感染，并且这个数字正在以每年 56,000 例新感染者的速度稳步增长（CDC 估计）。尽管抗逆转录病毒疗法取得了重要进展，并且有 30 多种药物可作为单一药物或组合药物使用，但副作用和多重耐药病毒的出现仍然对 HIV 治疗构成重大挑战。我们建议通过一种新的机制来识别和表征能够阻断艾滋病毒的抗逆转录病毒化合物。这些独特的化合物可用于治疗艾滋病毒感染。 。 PHS 398/2590（修订版 06/09） 页面延续 格式页面