Cell Penetrating Helical Peptide Inhibitors of vFLIP K13

vFLIP K13 的细胞穿透螺旋肽抑制剂

• 批准号: 8236941
• 负责人: Preet M. Chaudhary
• 金额: $ 38.89万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236941
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Amino Acids; Apoptosis; Binding; Biological Assay; Biological Process; CASP8 and FADD-like apoptosis regulating protein; CASP8 gene; Cell Line; Cell Proliferation; Cells; Chemicals; Clinical; Clinical Trials; Complex; Development; Disease; Future; Genetic; Genome; Goals; Growth Factor; Herpesviridae Infections; Human Herpesvirus 8; Hydrocarbons; Immune response; Immunocompromised Host; Immunosuppression; Immunotherapy; In Vitro; Induction of Apoptosis; Infection; Inflammatory Response; Kaposi Sarcoma; Laboratories; Large-Cell Immunoblastic Lymphoma; Lead; Link; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Multicentric Angiofollicular Lymphoid Hyperplasia; Mutagenesis; NF-kappa B; Names; Open Reading Frames; Pathogenesis; Pathway interactions; Patients; Peptides; Permeability; Phosphotransferases; Physiological; Play; Proteins; Regimen; Serum; Small Interfering RNA; Structure; Testing; Viral; Viral Proteins; Virus Inhibitors; Withdrawal; alpha helix; base; caspase-8; chemotherapy; cytokine; design; effusion; in vivo Model; inhibitor/antagonist; metaplastic cell transformation; next generation; novel; outcome forecast; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): Infection with the Kaposi's sarcoma associated herpesvirus (KSHV) has been linked to the occurrence of Kaposi's sarcoma (KS) and several lymphoproliferative disorders, such as primary effusion lymphoma (PEL), multicentric Castleman's disease and immunoblastic/plasmablastic lymphomas. Due to underlying immunosuppression, KSHV-associated cancers have extremely poor prognosis when treated with conventional chemotherapy and there is urgent need for more effective and less toxic therapies for these disorders. Previous studies from our laboratory have shown that KSHV-encoded viral FLICE inhibitory protein (vFLIP) K13 is a powerful activator of the NF-kB pathway and plays a key role in the pathogenesis of KSHV-associated malignancies. K13 activates the NF-kB pathway by directly interacting with the NEMO/IKK3 subunit of the IkB kinase (IKK) complex and utilizes this pathway to promote cellular survival, proliferation, transformation and cytokine secretion. The above studies have established NF-kB pathway as an important therapeutic target for the treatment of KSHV-associated malignancies. However, since NF-kB pathway plays a key role in normal immune and inflammatory responses, global inhibitors of this pathway are likely to lead to severe immunosuppression, thus limiting their potential clinical utility in KSHV-infected patients. The overall goal of this proposal is to design cell-permeable helical peptides capable of blocking K13-NEMO interaction and to test their ability to block K13-induced NF-kB using in vitro and in vivo models developed in our laboratory. It is hoped that such peptides will specifically block K13-induced NF-kB without interfering with the physiological activation of this pathway during normal immune and inflammatory response. PUBLIC HEALTH RELEVANCE: Kaposi's sarcoma associated herpesvirus (KSHV) is the commonest cause of malignancies among patients with AIDS. The goal of this project is to develop peptides that can block the activity of K13, a small protein encoded by KSHV. It is hoped that such peptides will have utility for the development of targeted therapies for KSHV-associated malignancies.

描述（由申请人提供）：卡波西肉瘤相关疱疹病毒（KSHV）感染与卡波西肉瘤（KS）和多种淋巴组织增生性疾病（例如原发性渗出性淋巴瘤（PEL）、多中心卡斯尔曼病和免疫母细胞/浆母细胞病）的发生有关淋巴瘤。由于潜在的免疫抑制，KSHV 相关癌症在采用常规化疗时预后极差，因此迫切需要针对这些疾病的更有效且毒性更低的疗法。我们实验室前期的研究表明，KSHV编码的病毒FLICE抑制蛋白（vFLIP）K13是NF-kB通路的强大激活剂，在KSHV相关恶性肿瘤的发病机制中发挥着关键作用。 K13 通过直接与 IkB 激酶 (IKK) 复合物的 NEMO/IKK3 亚基相互作用来激活 NF-kB 通路，并利用该通路促进细胞存活、增殖、转化和细胞因子分泌。上述研究已确立NF-kB通路作为治疗KSHV相关恶性肿瘤的重要治疗靶点。然而，由于 NF-kB 通路在正常免疫和炎症反应中发挥着关键作用，该通路的整体抑制剂可能会导致严重的免疫抑制，从而限制了其在 KSHV 感染患者中的潜在临床应用。该提案的总体目标是设计能够阻断 K13-NEMO 相互作用的细胞渗透性螺旋肽，并使用我们实验室开发的体外和体内模型测试其阻断 K13 诱导的 NF-kB 的能力。希望此类肽能够特异性阻断 K13 诱导的 NF-kB，而不干扰正常免疫和炎症反应过程中该通路的生理激活。 公共卫生相关性：卡波西肉瘤相关疱疹病毒 (KSHV) 是艾滋病患者中最常见的恶性肿瘤原因。该项目的目标是开发能够阻断 K13（KSHV 编码的一种小蛋白）活性的肽。希望此类肽可用于开发 KSHV 相关恶性肿瘤的靶向疗法。