Rapamycin enhanced efficacy of small-molecule HIV entry inhibitors

雷帕霉素增强小分子 HIV 进入抑制剂的功效

• 批准号: 7548012
• 负责人: Antony S. Dimitrov
• 金额: $ 29.36万
• 依托单位: PROFECTUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-23 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7548012
• 关键词: Acquired Immunodeficiency Syndrome; Adverse effects; Algorithms; Animals; Anti-HIV Agents; Anti-HIV Therapy; Antiviral Agents; Bioavailable; Biological Assay; Biological Availability; Blood Cells; CCR5 gene; CD4 Antigens; CXCR4 gene; Cell Cycle; Cells; Cessation of life; Characteristics; Chemokine (C-C Motif) Receptor 5; Class; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Commercial Sources; Development; Dose; Drug Combinations; Drug Formulations; Drug Prescriptions; Evaluation; Exhibits; Fee-for-Service Plans; Fuzeon; Goals; Government; Growth; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV Infections; HIV Receptors; HIV-1; Highly Active Antiretroviral Therapy; Human; Immunosuppressive Agents; In Vitro; Incidence; Infection; Kidney Transplantation; Licensing; Marketing; Maryland; Methods; Monitor; Morbidity - disease rate; Nucleosome Binding Domain; Oral; Performance; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phase; Predisposition; Process; Proteins; Public Health; Purpose; Relative (related person); Research Design; Resistance; Resistance development; Sirolimus; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Standards of Weights and Measures; Surface; System; T-20; T-Lymphocyte; Technology; Testing; Therapeutic; United States Food and Drug Administration; Universities; Variant; Viral; Viral Load result; Virus; Virus Diseases; Week; Work; chemokine receptor; drug development; drug resistant virus; improved; inhibitor/antagonist; mortality; novel; novel strategies; pre-clinical; preclinical study; prevent; research study; small molecule

DESCRIPTION (provided by applicant): Newer approaches to the treatment of HIV infection seek to block the entry of the virus into the cell by targeting different proteins engaged in the entry process. Possible targets for entry inhibition include the HIV envelope (Env) glycoproteins gp120 and gp41, the cellular receptor CD4, and the chemokine receptors CCR5 and CXCR4. Clinical trials have demonstrated anti-HIV potential of the entry inhibitors. However, they suffer from the same challenges as the other HAART drugs - rapid outgrowth of resistant virus and numerous side effects. Recently, cell cycle agents, such as rapamycin that downregulates the CCR5 receptor, were found to synergize with the entry inhibitor T20, one of the two entry inhibitors approved by the FDA, known also as Fuzeon or Enfuvirtide. Our preliminary experiments further demonstrate that the addition of rapamycin in vitro prevents the emergence of T20 resistant viruses and enhances the susceptibility to T20 of otherwise resistant viruses. We have also found that rapamycin synergizes with and enhances the anti-HIV efficiency of TAK-779, a small molecule CCR5 antagonist with potent antiviral activity. These observations suggest that rapamycin may enhance the therapeutic performance of other entry inhibitors such as selzentry, known as maraviroc, which, like TAK-779, targets CCR5. Selzentry has already been approved by the FDA on August 6, 2007 for anti-HIV therapy in combinations with other HAART drugs. The objective of this project, therefore, is to identify those small molecule entry inhibitors that are on the market and in advanced clinical or preclinical studies that show improved anti-HIV efficiency in the presence of rapamycin. We propose to reach the goal via the following 3 aims: Aim 1: Identify which of the selected small molecule entry inhibitors synergize with rapamycin to inhibit viral infections in human PBMCs; Aim 2: Demonstrate that the addition of rapamycin inhibits the outgrowth of inhibitor resistant viruses in vitro; Aim 3: Demonstrate that the addition of rapamycin can recover the susceptibility of the inhibitor resistant viruses. Should we identify compounds with the preceding characteristics during this Phase I project, our SBIR Phase II proposal will endeavor to develop an oral rapamycin/entry inhibitor co-formulation for treatment of HIV infection. This document contains proprietary information that Profectus BioSciences requests not be released to persons outside the Government, except for purposes of review and evaluation. PUBLIC HEALTH RELEVANCE Rapamycin (Wyeth, Madison, NJ) is an immunosuppressant drug prescribed for oral use after kidney transplantation. It is a cell cycle agent that downregulates the expression of CCR5 on the surface of activated T cells. In vitro, rapamycin enhances the efficacy of HIV entry inhibitors: T20 and TAK-779. This observation suggests that rapamycin may also enhance the potential of small molecule entry inhibitors that have already shown reasonable bioavailability. The objective of this project is to identify orally bioavailable entry inhibitors that are on the market, near market or in early clinical studies and that synergize with rapamycin in their anti-HIV efficiency. Such inhibitors will provide opportunities to develop novel orally administered formulations with enhanced antiviral efficiency. Preclinical and clinical development of such combinations will be the subject of follow-on SBIRs.

描述（由申请人提供）：治疗HIV感染的新方法试图通过靶向参与进入过程的不同蛋白质来阻止病毒进入细胞。进入抑制的可能靶点包括HIV包膜（Env）糖蛋白gp120和gp41、细胞受体CD4和趋化因子受体CCR5和CXCR4。临床试验证明了进入抑制剂的抗hiv潜力。然而，它们面临着与其他HAART药物相同的挑战——耐药病毒的快速生长和许多副作用。最近，细胞周期药物，如下调CCR5受体的雷帕霉素，被发现与进入抑制剂T20协同作用，T20是FDA批准的两种进入抑制剂之一，也被称为Fuzeon或Enfuvirtide。我们的初步实验进一步证明，体外添加雷帕霉素可以阻止T20耐药病毒的出现，并增强其他耐药病毒对T20的易感性。我们还发现雷帕霉素与具有强抗病毒活性的小分子CCR5拮抗剂TAK-779协同作用并增强其抗hiv效率。这些观察结果表明，雷帕霉素可能增强其他进入抑制剂的治疗效果，如selzentry，即maraviroc，与TAK-779一样，靶向CCR5。Selzentry已于2007年8月6日被FDA批准与其他HAART药物联合用于抗hiv治疗。因此，该项目的目标是确定那些在市场上和在高级临床或临床前研究中显示在雷帕霉素存在下抗艾滋病毒效率提高的小分子进入抑制剂。我们建议通过以下3个目标来实现这一目标：目标1：确定哪些选定的小分子进入抑制剂与雷帕霉素协同作用以抑制人PBMCs中的病毒感染；目的2：在体外证明添加雷帕霉素可抑制抑制剂耐药病毒的生长；目的3：证明添加雷帕霉素可以恢复抑制剂耐药病毒的敏感性。如果我们在I期项目中发现具有上述特征的化合物，我们的SBIR II期提案将努力开发用于治疗HIV感染的口服雷帕霉素/进入抑制剂联合制剂。本文件包含专有信息，除非用于审查和评估目的，否则Profectus BioSciences不要求向政府以外的人员发布。雷帕霉素（Wyeth, Madison， NJ）是肾移植后口服的一种免疫抑制药物。它是一种下调活化T细胞表面CCR5表达的细胞周期剂。在体外，雷帕霉素可以增强HIV进入抑制剂T20和TAK-779的疗效。这一观察结果表明，雷帕霉素也可能增强已经显示出合理生物利用度的小分子进入抑制剂的潜力。该项目的目标是确定已上市、接近上市或处于早期临床研究中的口服生物有效进入抑制剂，并与雷帕霉素协同作用，提高抗艾滋病毒的效率。这些抑制剂将为开发具有增强抗病毒效率的新型口服制剂提供机会。这些组合的临床前和临床开发将是后续SBIRs的主题。