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

丙型肝炎病毒和乙肝病毒是导致肝细胞癌的主要原因。患上肝细胞癌的风险仍然持平 在病毒清除后。因此，确定治疗病毒性肝炎的新方法是至关重要的- 诱导的肝细胞癌。我们鉴定了一类新的小分子化合物，称为生力素衍生物(SfDer)，它 具有抗病毒和抗细胞活性，对预防病毒性肝炎诱导的肝细胞癌发展至关重要。 最近的发现强调了我们的应用具有非常重要的意义：i)肝细胞癌是增长最快的事业 癌症死亡率；ii)最近的研究提出了一个危险信号，表明肝癌复发率意外上升 在DAA治疗后，表明病毒性肝炎相关的肝细胞癌仍然是一个未解决的和重要的 公共卫生问题；iii)患有肝癌的患者失败DAA治疗的可能性是没有接受DAA治疗的患者的8倍 肝细胞癌；iv)FDA证实在DAA治疗后乙肝病毒重新激活的高风险；以及v)除了索拉非尼， 仅可将存活率提高2-3个月，评估肝癌治疗方法的100项试验均未显示存活率 优势。因此，迫切需要识别具有不同特征的药物的新组合。 同时抑制丙型肝炎/乙肝病毒感染和病毒性肝炎诱导的肝细胞癌的作用机制(MOA)。 我们证明SfDer具有显著的活性，对治疗病毒性肝炎感染至关重要。 和肝癌：i)SfDer在体外和小鼠体内抑制丙型肝炎病毒和乙肝病毒的复制，即使在病毒复制时也是如此 移植的肝细胞是健壮的；ii)SfDer即使在高剂量使用时也没有细胞毒性；iii)SfDer，但不 另一类结构不同的亲环素抑制剂(CypI)-环孢素A衍生物(CsADer)-具有 阻止肝癌细胞生长的独特性质，但不能阻止肝细胞的生长；iv)SfDer体外抑制 体内丙型肝炎病毒和乙肝病毒在人肝细胞中的复制，对SfDer介导的 细胞统计学，显示与其细胞抑制活性无关的真实抗病毒活性；v)SfDer抑制 病毒性肝炎诱导的肝癌；vi)SfDer在非病毒诱导的肝癌小鼠模型中抑制肝癌；以及vii)SfDer 在肝细胞癌发展过程中调节肝脏细胞因子水平。因此，SfDer代表了新的有吸引力的药物 作为治疗丙型肝炎病毒和乙肝病毒单一和混合感染以及病毒性肝炎引起的肝细胞癌的一部分。 在目标1中，我们将研究SfDer对小鼠病毒性肝炎感染和肝癌诱导的抑制作用。我们 将研究将SfDer纳入DAA方案是否提高了它们对抗病毒的有益效果 肝炎感染与肝细胞癌的诱导，丙型肝炎病毒/乙肝病毒混合感染是否比单一感染引起更严重的肝细胞癌？ 感染，以及SfDer是否抑制联合感染和联合感染诱导的肝癌。在目标2中，我们将调查 新发现的亲环素A-HBx相互作用是否对乙肝病毒至关重要 复制。在目标3中，我们将研究SfDer在预防非病毒诱导的肝癌方面的有效性。我们也会 从分子水平研究允许SfDer阻止肝癌细胞(非肝细胞)生长的MOA-a 独特的性质，可能有助于其抗肝癌的作用。

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.