Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Hepion Pharmaceuticals Inc., Edison, NJ 08837, USA.
Viruses. 2023 Oct 17;15(10):2099. doi: 10.3390/v15102099.
There is an urgent need for the identification of new drugs that inhibit HCV-induced hepatocellular carcinoma (HCC). Our work demonstrates that cyclophilin inhibitors (CypIs) represent such new drugs. We demonstrate that the nonimmunosuppressive cyclosporine A (CsA) analog (CsAa) rencofilstat possesses dual therapeutic activities for the treatment of HCV infection and HCV-induced HCC. Specifically, we show that the HCV infection of humanized mice results in the progressive development of HCC. This is true for the four genotypes tested (1 to 4). Remarkably, we demonstrate that rencofilstat inhibits the development of HCV-induced HCC in mice even when added 16 weeks after infection when HCC is well established. Importantly, we show that rencofilstat drastically reduces HCC progression independently of its anti-HCV activity. Indeed, the CypI rencofilstat inhibits HCC, while other anti-HCV agents such as NS5A (NS5Ai) and NS5B (NS5Bi) fail to reduce HCC. In conclusion, this study shows for the first time that the CypI rencofilstat represents a potent therapeutic agent for the treatment of HCV-induced HCC.
迫切需要鉴定能够抑制 HCV 诱导的肝细胞癌 (HCC) 的新药。我们的工作表明，亲环素抑制剂 (CypI) 就是这样的新药。我们证明，非免疫抑制性环孢素 A (CsA) 类似物 (CsAa) rencofilstat 具有治疗 HCV 感染和 HCV 诱导的 HCC 的双重治疗活性。具体而言，我们表明，HCV 感染人源化小鼠会导致 HCC 的进行性发展。这适用于测试的四种基因型 (1 至 4)。值得注意的是，我们证明 rencofilstat 甚至在感染 16 周后 HCC 已经确立时，也能抑制 HCV 诱导的 HCC 在小鼠中的发展。重要的是，我们表明 rencofilstat 可独立于其抗 HCV 活性明显降低 HCC 的进展。事实上，CypI rencofilstat 抑制 HCC，而其他抗 HCV 药物如 NS5A (NS5Ai) 和 NS5B (NS5Bi) 则不能降低 HCC。总之，这项研究首次表明，CypI rencofilstat 是治疗 HCV 诱导的 HCC 的有效治疗药物。
