Shimura Satomi, Watashi Koichi, Fukano Kento, Peel Michael, Sluder Ann, Kawai Fumihiro, Iwamoto Masashi, Tsukuda Senko, Takeuchi Junko S, Miyake Takeshi, Sugiyama Masaya, Ogasawara Yuki, Park Sam-Yong, Tanaka Yasuhito, Kusuhara Hiroyuki, Mizokami Masashi, Sureau Camille, Wakita Takaji
Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; SCYNEXIS, Inc., Durham, NC 27713, USA.
Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Applied Biological Science, Tokyo University of Sciences, Noda 278-8510, Japan; CREST, Japan Science and Technology Agency (J.S.T.), Saitama 332-0012, Japan.
J Hepatol. 2017 Apr;66(4):685-692. doi: 10.1016/j.jhep.2016.11.009. Epub 2016 Nov 25.
BACKGROUND & AIMS: The sodium taurocholate co-transporting polypeptide (NTCP) is the main target of most hepatitis B virus (HBV) specific entry inhibitors. Unfortunately, these agents also block NTCP transport of bile acids into hepatocytes, and thus have the potential to cause adverse effects. We aimed to identify small molecules that inhibit HBV entry while maintaining NTCP transporter function.
We characterized a series of cyclosporine (CsA) derivatives for their anti-HBV activity and NTCP binding specificity using HepG2 cells overexpressing NTCP and primary human hepatocytes. The four most potent derivatives were tested for their capacity to prevent HBV entry, but maintain NTCP transporter function. Their antiviral activity against different HBV genotypes was analysed.
We identified several CsA derivatives that inhibited HBV infection with a sub-micromolar IC. Among them, SCY446 and SCY450 showed low activity against calcineurin (CN) and cyclophilins (CyPs), two major CsA cellular targets. This suggested that instead, these compounds interacted directly with NTCP to inhibit viral attachment to host cells, and have no immunosuppressive function. Importantly, we found that SCY450 and SCY995 did not impair the NTCP-dependent uptake of bile acids, and inhibited multiple HBV genotypes including a clinically relevant nucleoside analog-resistant HBV isolate.
This is the first example of small molecule selective inhibition of HBV entry with no decrease in NTCP transporter activity. It suggests that the anti-HBV activity can be functionally separated from bile acid transport. These broadly active anti-HBV molecules are potential candidates for developing new drugs with fewer adverse effects.
In this study, we identified new compounds that selectively inhibited hepatitis B virus (HBV) entry, and did not impair bile acid uptake. Our evidence offers a new strategy for developing anti-HBV drugs with fewer side effects.
牛磺胆酸钠共转运多肽（NTCP）是大多数乙型肝炎病毒（HBV）特异性进入抑制剂的主要靶点。不幸的是，这些药物也会阻断胆汁酸通过NTCP转运进入肝细胞，因此有可能产生不良反应。我们旨在鉴定出在维持NTCP转运蛋白功能的同时抑制HBV进入的小分子。
我们使用过表达NTCP的HepG2细胞和原代人肝细胞，对一系列环孢素（CsA）衍生物的抗HBV活性和NTCP结合特异性进行了表征。测试了四种最有效的衍生物阻止HBV进入但维持NTCP转运蛋白功能的能力。分析了它们对不同HBV基因型的抗病毒活性。
我们鉴定出几种CsA衍生物，它们以亚微摩尔IC抑制HBV感染。其中，SCY446和SCY450对钙调神经磷酸酶（CN）和亲环蛋白（CyP）这两个主要的CsA细胞靶点活性较低。这表明，这些化合物反而直接与NTCP相互作用，以抑制病毒附着于宿主细胞，且没有免疫抑制功能。重要的是，我们发现SCY450和SCY995不会损害胆汁酸的NTCP依赖性摄取，并能抑制多种HBV基因型，包括临床上相关的核苷类似物耐药HBV分离株。
这是小分子选择性抑制HBV进入且NTCP转运蛋白活性不降低的首个实例。这表明抗HBV活性在功能上可与胆汁酸转运分离。这些具有广泛活性的抗HBV分子是开发副作用较少的新药的潜在候选物。
在本研究中，我们鉴定出了选择性抑制乙型肝炎病毒（HBV）进入且不损害胆汁酸摄取的新化合物。我们的证据为开发副作用较少的抗HBV药物提供了新策略。
