Cell Penetrating Helical Peptide Inhibitors of vFLIP K13

描述(由申请人提供)：感染卡波西肉瘤相关疱疹病毒(KSHV)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相关癌症在接受常规化疗时预后极差，迫切需要更有效、毒性更低的治疗方法。本实验室以往的研究表明，KSHV编码的病毒FLICE抑制蛋白(VFLIP)K13是一种强大的核因子-kB途径激活剂，在KSHV相关恶性肿瘤的发病机制中起着关键作用。K13通过直接与IKB激酶(IKK)复合体的Nemo/IKK3亚基相互作用来激活核因子-kB途径，并利用这一途径促进细胞的生存、增殖、转化和细胞因子的分泌。以上研究为KSHV相关恶性肿瘤的治疗提供了重要靶点。然而，由于核因子-kB通路在正常的免疫和炎症反应中起关键作用，该通路的全局抑制剂很可能导致严重的免疫抑制，从而限制其在KSHV感染患者中的潜在临床应用。这项建议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，并利用我们实验室建立的体外和体内模型来测试它们阻断K13诱导的NF-kB的能力。在正常的免疫和炎症反应中，这些多肽有望在不干扰这一途径的生理激活的情况下，特异性地阻断K13诱导的核因子-kB。

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.