Cell Penetrating Helical Peptide Inhibitors of vFLIP K13

描述（由申请方提供）：卡波西肉瘤相关疱疹病毒（KSHV）感染与卡波西肉瘤（KS）和几种淋巴增生性疾病的发生有关，如原发性渗出性淋巴瘤（PEL）、多中心Castleman病和免疫母细胞/浆母细胞淋巴瘤。由于潜在的免疫抑制，KSHV相关癌症在用常规化疗治疗时具有极差的预后，并且迫切需要针对这些疾病的更有效且毒性更小的疗法。我们实验室以前的研究表明，KSHV编码的病毒FLICE抑制蛋白（vFLIP）K13是NF-κ B通路的强大激活剂，在KSHV相关恶性肿瘤的发病机制中起着关键作用。K13通过与IkB激酶（IKK）复合物的NEMO/IKK 3亚基直接相互作用激活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-κ B通路作为KSHV相关恶性肿瘤治疗的重要靶点。然而，由于NF-κ B通路在正常的免疫和炎症反应中起着关键作用，该通路的全局抑制剂可能导致严重的免疫抑制，从而限制了它们在KSHV感染患者中的潜在临床应用。本提案的总体目标是设计能够阻断K13-NEMO相互作用的细胞可渗透的螺旋肽，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-κ B的能力。希望这些肽将特异性阻断K13诱导的NF-kB，而不干扰正常免疫和炎症反应期间该途径的生理活化。 公共卫生相关性：卡波西肉瘤相关疱疹病毒（KSHV）是艾滋病患者恶性肿瘤的最常见原因。该项目的目标是开发可以阻断K13活性的肽，K13是KSHV编码的一种小蛋白。人们希望，这样的肽将有效用的KSHV相关的恶性肿瘤的靶向治疗的发展。

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.