以宿主蛋白APE1为靶点的抗KSHV及相关肿瘤的药物研究

KSHV is a DNA virus associated with Kaposis Sarcoma(KS),primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD).KS is the most common tumor in AIDS-patients which can cause high fatality. KS is also an angiogenic and invasive tumor and abnormal neovascular channel that fills with red blood cells is a pathological feature of KS. Traditional therapy strategy is not an available cure for KS. There is an emergency to find some new target to specially block KS through its causative agent KSHV. APE-1 is a multifunctional protein that carries a DNA base excision repair function in its C-domain (acting as apurinic/apyrimidinic endonuclease) and a redox activity in its N-terminal domain, which maintains the reduced state of its substrate transcription factors and increases their DNA binding abilities. The transcription factors that need APE-1 for DNA binding include AP-1, NF-κB, Erg-1, HIF-1a, COX-2, p53.Many of them are crucial in the progression of KS. Our previous research had demonstrated that APE1 play a big role in KSHV lytic replication and pathogenic phenotypes, through a virtual screening we used an in-house three-dimensional (3D) molecular superimposing algorithm and yielded a natural product compound, C10, which shows binding potential to APE-1 at the N terminal domain and specially block the redox activity of APE1. C10 could efficiently block KSHV lytic replication and KSHV-mediated neoangiogenesis of oral MSCs as shown in vitro matrigel tubule formation assay and ex vivo matrigel plug assay. During this research, we plan to indentify the activity of C10 blocking MHV-68 ,which is a homology herpersvirous of KSHV, lytic replication and KS progression in animal model in vivo and to further understand the mechanism of C10 block KSHV induced KS progresision in order to push this compound to pro-clinic research.

KSHV能引起人类产生恶性肿瘤。KSHV引起的肿瘤包括卡波氏肉瘤，原发性渗出性淋巴瘤和多中心 Castleman病。KS肿瘤处常表现为丰富的血管增生和炎症因子浸润。传统治疗KS的方法如放疗、化疗对KS的疗效不好。APE1是一个多功能的蛋白，C端控制DNA修复功能，N端调控转录因子的氧化还原能力。APE1下游调控的转录因子在KS促进肿瘤发展的进程中发挥作用。APE1是治疗KS的一个有效的靶点。早期研究中，我们已经筛选出一种全新结构的APE1的N端抑制剂C10，C10可以高效的抑制KSHV的裂解复制和KSHV促进肿瘤发生的表型。如：C10可以抑制KSHV诱导的血管新生和细胞侵袭能力。我们将进一步评价C10对鼠疱疹病毒在小鼠体内进行裂解复制的药效以及C10对小鼠体内KS样肿瘤形成过程的药效，并在细胞水平和动物水平解释C10抑制KS肿瘤形成的作用机制。为C10的临床前研究提供理论依据。

KSHV是重要的致瘤病毒，KSHV的感染引发多种恶性肿瘤，包括卡波西氏肉瘤，原发性渗出性淋巴瘤和多中心Castleman病。KSHV相关肿瘤，尤其是卡波西氏肉瘤表现为丰富的血管新生和炎症细胞浸润。我们期望通过靶向肿瘤的血管新生、迁移侵袭等特性寻找抑制KSHV相关肿瘤的特效药。早期研究中，我们筛选出一种全新结构的APE1的N端抑制剂C10，C10可以高效的抑制KSHV的裂解复制和KSHV诱导的肿瘤表型。在此基础上，本项目完成了以下研究：（1）阐明 APE1 抑制剂 C10 抑制 KSHV 诱导的血管新生和侵袭能力的作用机理。（2）在细胞水平和活体水平检测了C10对γ疱疹病毒的抑制作用，并评价了其毒性。（3）成功构建了KSHV相关肿瘤模型，为APE1抑制剂C10的临床前研究奠定了基础。