Cell Penetrating Helical Peptide Inhibitors of vFLIP K13

描述（由申请人提供）：卡波西氏肉瘤相关疱疹病毒（KSHV）感染与卡波西氏肉瘤（KS）和几种淋巴增生性疾病（如原发性积液淋巴瘤（PEL）、多中心Castleman病和免疫母细胞/浆母细胞淋巴瘤）的发生有关。由于潜在的免疫抑制，kshv相关癌症在常规化疗治疗时预后极差，迫切需要更有效、毒性更小的治疗方法。我们实验室之前的研究表明，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起关键作用。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。以上研究都确立了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起关键作用，该通路的全局抑制剂可能导致严重的免疫抑制，从而限制了其在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它们阻断k13诱导的NF-kB的能力。希望这些肽能够特异性阻断k13诱导的NF-kB，而不会干扰正常免疫和炎症反应中该途径的生理激活。

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.