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Non-immunosuppressive Sanglifehrin Analogs as Therapeutic Agents for Viral Hepatitis-induced Liver Damage Development

非免疫抑制性桑非菌素类似物作为病毒性肝炎引起的肝损伤发展的治疗剂

基本信息

批准号：
10374889
负责人：
PHILIPPE ANDRE GALLAY
金额：
$ 44.38万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374889
关键词：
Antiviral Agents Awareness BAY 54-9085 Biological Markers Cancer Etiology Cessation of life Complex Congresses Cyclophilin A Cyclophilins Cyclosporine Cytostatics Development Dose Funding Growth Hepatic Hepatitis B Infection Hepatitis B Virus Hepatitis C Hepatitis C Therapy Hepatitis C virus Hepatocyte Human Implant In Vitro Incidence Infection Infection prevention Inflammatory Link Malignant neoplasm of liver Mediating Membrane Molecular Mus Nocodazole Patients Pharmaceutical Preparations Primary carcinoma of the liver cells Property Public Health RNA replication Recurrence Regimen Reporting Research Resistance Risk TP53 gene Therapeutic Therapeutic Agents Time Vesicle Viral Viral hepatitis Virus Virus Replication analog anticancer activity cell growth chemotherapy co-infection cytokine experimental study hepatoma cell high risk improved in vivo inhibitor liver injury mortality mouse model novel novel drug combination novel strategies novel therapeutic intervention novel therapeutics prevent sanglifehrin A targeted treatment tool treatment duration viral RNA

项目摘要

HCV and HBV represent the leading cause of hepatocellular carcinoma (HCC). The risk of HCC remains even after virus elimination. Thus, it is of the utmost importance to identify novel approaches to treat viral hepatitis- induced HCC. We identified a novel class of small compounds called sanglifehrin derivates (SfDer), which possess antiviral and anti-cellular activities critical for preventing viral hepatitis-induced HCC development. Recent findings highlight that our application is highly significant: i) HCC represents the fastest growing cause of cancer mortality; ii) Recent studies raised a red flag regarding unexpected higher rates of HCC recurrence following DAA treatment, indicating that viral hepatitis-associated HCC remains an unresolved and significant public health issue; iii) Patients with HCC are 8 times more likely to fail DAA treatment than patients without HCC; iv) The FDA confirmed the high risk of HBV reactivation after DAA therapy; and v) Besides sorafenib, which improves survival by only 2-3 months, >100 trials evaluating therapies for HCC failed to show survival advantages. Therefore, there is an urgent need for the identification of new combinations of drugs with distinct mechanisms of action (MoA) that concurrently inhibit HCV/HBV infections and viral hepatitis-induced HCC. We demonstrated that SfDer possess remarkable activities critical for the treatment of viral hepatitis infection and HCC: i) SfDer suppress HCV and HBV replication in vitro as well as in mice even when viral replication in implanted hepatocytes is robust; ii) SfDer are not cytotoxic even when used at high doses; iii) SfDer, but not another class of structurally distinct cyclophilin inhibitors (CypI) – cyclosporine A derivates (CsADer) – possess the unique property of stopping growth of hepatoma cells, but not that of hepatocytes; iv) SfDer inhibit in vitro and in vivo HCV and HBV replication in human hepatocytes, which are resistant to the SfDer-mediated cytostaticity, demonstrating authentic antiviral activities unrelated to their cytostatic activities; v) SfDer inhibit viral hepatitis-induced HCC; vi) SfDer inhibit HCC in a nonviral-induced HCC mouse model; and vii) SfDer modulate hepatic levels of cytokines during HCC development. Thus, SfDer represent novel attractive drugs to be part of therapies for HCV and HBV mono- and co-infections as well as viral hepatitis-induced HCC. In Aim 1, we will investigate SfDer efficacy at inhibiting viral hepatitis infection and HCC induction in mice. We will examine whether the inclusion of SfDer into DAA regimens improves their beneficial effect against viral hepatitis infection and HCC induction, whether HCV/HBV co-infection induces more severe HCC than mono- infection, and whether SfDer inhibit co-infection and co-infection-induced HCC. In Aim 2, we will investigate whether the newly identified cyclophilin A-HBx interactions, which are prevented by SfDer, are critical for HBV replication. In Aim 3, we will investigate the efficacy of SfDer at preventing nonviral-induced HCC. We also will investigate at a molecular level the MoA that allow SfDer to stop hepatoma cell growth (not hepatocytes) – a unique property that may contribute to their anti-HCC impact.

HCV 和 HBV 是导致肝细胞癌 (HCC) 的主要原因。肝癌的风险仍然均匀病毒消灭后。因此，寻找治疗病毒性肝炎的新方法至关重要诱发肝癌。我们发现了一类新型小化合物，称为桑菲林衍生物 (SfDer)，它具有抗病毒和抗细胞活性，对于预防病毒性肝炎诱发的肝癌发展至关重要。最近的研究结果强调我们的应用非常重要：i) HCC 是增长最快的原因癌症死亡率； ii) 最近的研究对 HCC 复发率意外升高提出了危险信号 DAA 治疗后，表明病毒性肝炎相关的 HCC 仍然是一个尚未解决的重要问题公共卫生问题； iii) 患有 HCC 的患者 DAA 治疗失败的可能性是没有患 HCC 的患者的 8 倍肝癌； iv) FDA确认DAA治疗后存在HBV再激活的高风险； v) 除了索拉非尼之外，仅将生存率提高 2-3 个月，超过 100 项评估 HCC 疗法的试验未能显示生存率优点。因此，迫切需要鉴定具有独特作用的新药物组合。同时抑制 HCV/HBV 感染和病毒性肝炎诱发的 HCC 的作用机制 (MoA)。我们证明 SfDer 具有对于治疗病毒性肝炎感染至关重要的显着活性和 HCC：i) SfDer 在体外以及小鼠体内抑制 HCV 和 HBV 复制，即使病毒在体内复制植入的肝细胞坚固； ii) SfDer 即使在高剂量使用时也不具有细胞毒性； iii) SfDer，但不是另一类结构不同的亲环蛋白抑制剂 (CypI) – 环孢素 A 衍生物 (CsADer) – 具有阻止肝癌细胞生长但不阻止肝细胞生长的独特特性； iv) SfDer 体外抑制以及对 SfDer 介导的抗性的人肝细胞中的体内 HCV 和 HBV 复制细胞抑制性，表现出与其细胞抑制活性无关的真实抗病毒活性； v) SfDer 抑制病毒性肝炎诱发的肝癌； vi) SfDer 在非病毒诱导的 HCC 小鼠模型中抑制 HCC；和 vii) SfDer 在 HCC 发展过程中调节肝脏细胞因子水平。因此，SfDer 代表新颖有吸引力的药物成为 HCV 和 HBV 单一感染和混合感染以及病毒性肝炎诱发的 HCC 治疗的一部分。在目标 1 中，我们将研究 SfDer 在抑制小鼠病毒性肝炎感染和肝癌诱导方面的功效。我们将检查将 SfDer 纳入 DAA 方案是否可以提高其对抗病毒的有益效果肝炎感染和 HCC 诱发，HCV/HBV 合并感染是否比单一感染诱发更严重的 HCC 感染，以及 SfDer 是否抑制合并感染和合并感染诱导的 HCC。在目标 2 中，我们将调查新发现的亲环蛋白 A-HBx 相互作用（被 SfDer 阻止）是否对 HBV 至关重要复制。在目标 3 中，我们将研究 SfDer 在预防非病毒诱发的 HCC 方面的功效。我们也会在分子水平上研究使 SfDer 能够阻止肝癌细胞（而非肝细胞）生长的 MoA – 可能有助于其抗 HCC 作用的独特特性。