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

HCV和HBV代表肝细胞癌（HCC）的主要原因。HCC的风险仍然是 病毒消除后。因此，确定治疗病毒性肝炎的新方法至关重要- 诱发HCC。我们发现了一类新的小化合物，称为sanglifehrin衍生物（SfDer）， 具有对于预防病毒性肝炎诱导的HCC发展至关重要的抗病毒和抗细胞活性。 最近的研究结果强调，我们的应用是非常重要的：i）HCC代表增长最快的原因 ii）最近的研究对HCC复发率意外升高发出了警告 DAA治疗后，表明病毒性肝炎相关的HCC仍然是一个未解决的和重要的 公共卫生问题; iii）HCC患者DAA治疗失败的可能性是未接受DAA治疗的患者的8倍。 HCC; iv）FDA证实了DAA治疗后HBV再激活的高风险;和v）除了索拉非尼， 这只提高了2-3个月的生存率，超过100项评估HCC治疗的试验未能显示生存率 优势因此，迫切需要鉴定具有不同的抗肿瘤活性的新的药物组合。 同时抑制HCV/HBV感染和病毒性肝炎诱导的HCC的作用机制（MoA）。 我们证明SfDer具有显著的活性，对于治疗病毒性肝炎感染至关重要 i）SfDer在体外以及在小鼠中抑制HCV和HBV复制，即使当在小鼠中病毒复制时也是如此。 植入的肝细胞是稳健的; ii）SfDer即使在高剂量下使用时也没有细胞毒性; iii）SfDer，但没有细胞毒性。 另一类结构不同的亲环蛋白抑制剂（CypI）-环孢菌素A衍生物（CsADer）-具有 具有阻止肝癌细胞生长而不阻止肝细胞生长的独特性质; iv）SfDer体外抑制 以及体内HCV和HBV在人肝细胞中的复制，其对SfDer介导的 细胞抑制活性，证明与其细胞抑制活性无关的真实抗病毒活性; 病毒性肝炎诱导的HCC; vi）SfDer在非病毒诱导的HCC小鼠模型中抑制HCC;和vii）SfDer 在HCC发展过程中调节肝细胞因子水平。因此，SfDer代表了新的有吸引力的药物 作为HCV和HBV单一感染和合并感染以及病毒性肝炎诱导的HCC治疗的一部分。 在目的1中，我们将研究SfDer在抑制小鼠病毒性肝炎感染和HCC诱导方面的功效。我们 将检查是否SfDer纳入DAA方案改善其对病毒的有益作用， 肝炎感染和HCC诱导，HCV/HBV合并感染是否比单一感染诱导更严重的HCC， 感染，以及SfDer是否抑制共感染和共感染诱导的HCC。在目标2中，我们将研究 新发现的亲环素A-HBx相互作用（SfDer可阻止）是否对HBV至关重要 复制的在目标3中，我们将研究SfDer预防非病毒诱导的HCC的疗效。我们也将 在分子水平上研究允许SfDer停止肝癌细胞生长（而不是肝细胞）的MoA- a 这可能有助于其抗HCC作用的独特性质。

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.