Novel Anti-HCMV Strategies

新的抗 HCMV 策略

• 批准号: 9918444
• 负责人: Gary Ching Tao Chan
• 金额: $ 74.37万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918444
• 关键词: Ablation; Advocate; Affinity; Antiviral Agents; Apoptosis; BCL-2 Protein; BCL2 gene; Binding; Blood Circulation; Cell surface; Cells; Cessation of life; Charge; Chronic; Clinical; Cytomegalovirus; Development; Disease; Drug Design; Encapsulated; Exhibits; Failure; Formulation; Functional disorder; Growth Factor; Heart; Heart-Lung Transplantation; Hematogenous; Human; Human Herpesvirus 4; Incidence; Infection; Inflammation; Inflammatory; Kinetics; Laboratories; Lead; Libraries; Lung; MCL1 gene; Morbidity - disease rate; Myelogenous; Myeloid Cells; Nature; Opportunistic Infections; Organ; Organ Transplantation; Peripheral; Phagocytes; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Prophylactic treatment; Protein Family; Reporting; Role; Series; Site; Solid; Specificity; Structure; Surface; Technology; Testing; Therapeutic; Tissues; Transplant Recipients; Transplantation; Viral; Virus; Virus Replication; analog; base; cell type; cytotoxicity; design; high risk; high throughput screening; humanized mouse; improved; infected B cell; infection risk; inflammatory milieu; inhibitor/antagonist; macrophage; member; monocyte; mouse model; nanocarrier; nanoformulation; nanoparticle; neoplastic cell; novel; novel therapeutics; outcome forecast; prevent; prophylactic; screening; small molecule; small molecule inhibitor; virtual

PROJECT SUMMARY Human cytomegalovirus (HCMV) is the single most important infection leading to transplant failure and continues to be a cause of substantial morbidity and death. Indeed, HCMV disease occurs in 20-30% of transplants at risk for infection and is a particular problem to lung or heart-lung recipients with a reported incidence of 50-80%. Clinical manifestations of HCMV are widespread, inflammatory in nature, and dependent on end-organ dysfunction. Inflammatory organ diseases associated with a HCMV infection is a direct consequence of the systemic viral spread to and infection of multiple organ sites that occur during either asymptomatic or symptomatic infections. Monocytes are responsible for delivering the virus into tissue and play a central role in the inflammatory state of infected organs. Since therapies against HCMV are designed to block specific steps along the virus replication cycle, the lack of HCMV replication in infected blood monocytes indicates that HCMV antiviral drugs are not effective in preventing the initial spread of the virus. In accord, prophylaxis has simply shifted the kinetics of HCMV disease to later after transplantation due to the inability of antiviral drugs to eliminate infiltrating infected inflammatory myeloid cells, which are the principle cell type found in infected organs of transplant patients. Thus, we advocate that the suppression of HCMV replication with prophylactic antiviral drugs must be administered in combination with novel drugs specifically capable of killing infected monocytes. We have found that HCMV explicitly utilizes cellular Mcl-1, an antiapoptotic member of the Bcl-2 family of proteins, to stimulate the survival of infected monocytes. Using a high- throughput screening approach, Dr. Nikolovska-Coleska’s laboratory has synthesized and characterized two novel classes of highly selective Mcl-1 antagonists. We have tested one lead compound from each class of inhibitor and demonstrated both to have high killing activity towards HCMV-infected monocytes. Furthermore, we were able to significantly enhance the selectivity and killing activity of each compound by encapsulation into nanoparticles developed in Dr. Luo’s laboratory. Thus, we hypothesize that Mcl-1 inhibitors will target HCMV- infected monocytes to prevent hematogenous dissemination, which will be tested in 3 separate aims. Aim 1 will further evaluate the two library classes of Mcl-1 small-molecule inhibitors to identify compounds exhibiting maximum cytotoxicity against HCMV-infected monocytes. Medicinal chemistry will also be preformed to increase the potency of compounds. Aim 2 will be to further develop and characterize nanoparticle technology to enhance targeting of Mcl-1 inhibitors towards infected monocytes. Aim 3 will determine the efficacy of free versus encapsulated Mcl-1 small-molecule inhibitors at neutralizing/limiting HCMV spread in a humanized mouse model. These studies will evaluate the use of Mcl-1 inhibitors as an antiviral strategy to target infected cells rather than the virus directly, which could have major impact on the prognosis of transplant patients at high-risk for HCMV infection.

项目摘要 人巨细胞病毒（HCMV）是导致移植失败的单一最重要的感染， 仍然是造成大量发病和死亡的一个原因。事实上，HCMV疾病发生在20-30%的 移植有感染的风险，并且对于肺或心肺接受者来说是一个特别的问题， 发病率为50- 80%。HCMV的临床表现是广泛的，炎性的，依赖于 终末器官功能障碍与HCMV感染相关的炎症性器官疾病是一种直接的 在以下任一期间发生的全身性病毒扩散到多个器官部位和感染的后果 无症状或有症状的感染者。单核细胞负责将病毒递送到组织中， 在受感染器官的炎症状态中起核心作用。由于针对HCMV的疗法旨在 阻断沿着病毒复制周期的特定步骤，使HCMV在受感染的血液单核细胞中缺乏复制 表明HCMV抗病毒药物不能有效阻止病毒的最初传播。在雅阁中， 预防只是将HCMV疾病的动力学转移到移植后， 抗病毒药物，以消除浸润感染的炎性骨髓细胞，这是主要的细胞类型 在移植病人受感染的器官中发现的因此，我们主张抑制HCMV复制 预防性抗病毒药物必须与特异性能够 杀死受感染的单核细胞。我们发现HCMV明确利用细胞Mcl-1（一种抗凋亡蛋白） Bcl-2蛋白家族成员，以刺激受感染单核细胞的存活。使用高- Nikolovska-Coleska博士的实验室采用通量筛选方法合成并表征了两种 新型高选择性Mcl-1拮抗剂。我们已经测试了每一类中的一种铅化合物， 抑制剂，并证明两者对HCMV感染的单核细胞具有高杀伤活性。此外，委员会认为， 我们能够通过将每种化合物包封到 纳米粒子在罗博士的实验室开发。因此，我们假设Mcl-1抑制剂将靶向HCMV-1。 感染的单核细胞，以防止血行播散，这将在3个单独的目标进行测试。要求1 将进一步评估Mcl-1小分子抑制剂的两个文库类别以鉴定表现出以下特征的化合物： 对HCMV感染的单核细胞的最大细胞毒性。药物化学也将进行， 增加化合物的效力。目标2将是进一步发展和表征纳米粒子技术 以增强Mcl-1抑制剂对感染的单核细胞的靶向。目标3将确定免费的有效性 与包封的Mcl-1小分子抑制剂相比，在人源化细胞中中和/限制HCMV扩散。 小鼠模型这些研究将评估Mcl-1抑制剂作为靶向感染的抗病毒策略的用途。 细胞，而不是病毒直接，这可能对移植患者的预后产生重大影响， HCMV感染高危人群。