Cell Penetrating Helical Peptide Inhibitors of vFLIP K13

vFLIP K13 的细胞穿透螺旋肽抑制剂

• 批准号: 8440211
• 负责人: Preet M. Chaudhary
• 金额: $ 37.34万
• 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/8440211
• 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; 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; in vivo Model; inhibitor/antagonist; metaplastic cell transformation; next generation; novel; outcome forecast; primary effusion lymphoma; 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.

描述（由申请人提供）：与Kaposi肉瘤相关的疱疹病毒（KSHV）感染与Kaposi的肉瘤（KS）和几种淋巴细胞增生性疾病的发生有关淋巴瘤。由于潜在的免疫抑制，当接受常规化学疗法治疗时，KSHV相关的癌症的预后较差，并且迫切需要对这些疾病进行更有效且毒性更少的疗法。我们实验室的先前研究表明，KSHV编码的病毒抑制蛋白（VFLIP）K13是NF-KB途径的强大激活剂，并且在KSHV相关的恶性肿瘤的发病机理中起关键作用。 K13通过与IKB激酶（IKK）复合物的NeMo/IKK3亚基直接相互作用来激活NF-KB途径，并利用该途径来促进细胞存活，增殖，转化和细胞因子分泌。上述研究已将NF-KB途径确立为治疗与KSHV相关的恶性肿瘤的重要治疗靶点。但是，由于NF-KB途径在正常免疫和炎症反应中起关键作用，因此该途径的全球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效用。该提案的总体目标是设计能够阻止K13-NEMO相互作用的可渗透细胞的螺旋肽，并测试使用实验室中开发的体外和体内模型阻止K13诱导的NF-KB的能力。希望这种肽能特异性地阻断K13诱导的NF-KB，而不会在正常的免疫和炎症反应过程中干扰该途径的生理激活。