Hepatoselective Dihydroquinolizinone (HS-DHQ) Molecules for Treatment and Prevention of Hepatitis A Virus (HAV) Infection

用于治疗和预防的肝选择性二氢喹嗪酮（HS-HS-DHQ）分子 甲型肝炎病毒感染 摘要 这是一个I期提案，以开发Harlingene的肝选择性二氢喹嗪酮（HS- DHQs）用于治疗和预防甲型肝炎病毒（HAV）感染。这将是第一 抗病毒治疗治疗甲型肝炎病毒感染，尽管疫苗可以预防疾病， 在美国DHQ，每年有数千人住院治疗和许多人死亡， 罗氏公司的化合物RG 7834已被证明是有效的抗B型肝炎病毒（HBV）的药物。 并且已经由许多小型和大型制药公司开发用于HBV 企业我们率先开发DHQ用于治疗和预防肝炎 A.我们已经证明DHQ在细胞培养物和小鼠中对HAV具有高度活性。DHQ抑制 核苷酸转移酶TENT 4 A/B，也称为PAPD 7/5，其在细胞mRNA中起作用 “质量控制”和非编码转录物代谢，是有效的HBV和 HAV RNA功能。然而，它们对HBV和HAV的作用机制是不同的： DHQ促进HBV mRNA的降解，但不影响HAV RNA的稳定性。而不是DHQ 抑制HAV RNA合成。病毒转录物对DHQ的选择敏感性 为抗病毒治疗提供了一种低耐药风险的新策略。然而，DHQ 由于长期的神经毒性问题， 术语动物研究。因此，我们产生了一个肝选择性HS-DHQ家族， 受体富集在肝细胞上以实现肝选择性分布。我们领先的HS-DHQs 2 和3已显示在细胞培养物中具有抗HAV的纳米摩尔活性，并且它们靶向 培养物中的肝细胞，并在小鼠的肝脏中富集。我们现在合成了一个 HS-DHQ以优化其PK特征。我们的小鼠研究表明有效的治疗肝炎 A将只需要短暂的抗病毒治疗，我们建议我们的HS-DHQ具有更少的血浆和 在这种情况下使用时，其他组织接触将具有较低的神经毒性风险。在本STTR中 第一阶段的应用，我们将进行铅优化，以推进HS-DHQ不仅基于 组织培养中的抗HAV功效和PK研究结果，以及使用 用原代大鼠神经元进行体外测定和在神经元组织中体内分布。最好的HS- DHQs将进一步研究其在治疗和预防小鼠HAV感染中的功效。 然后将在HAV的鼠模型中具有最佳抗病毒、PK和PD性能的HS-DHQ进行如下研究： 通过支持人体临床研究所需的II期临床前研究取得进展。

Hepatoselective Dihydroquinolizinone (HS-HS-DHQ) Molecules for Treatment and Prevention of Hepatitis A Virus Infection ABSTRACT This is a Phase I proposal to develop Harlingene’s hepatoselective dihydroquinolizinones (HS- DHQs) for treatment and prevention of hepatitis A virus (HAV) infection. This will be the first antiviral therapy to treat HAV infection, which, despite vaccines to prevent disease, causes thousands of hospitalizations and many deaths each year in the U.S. DHQs, exemplified by the Roche compound, RG7834, have been shown to be effective antivirals for hepatitis B virus (HBV) and have been under development for HBV by a number of small and major pharmaceutical companies. We are pioneering development of DHQs for treatment and prevention of hepatitis A. We have shown DHQs are highly active against HAV in cell culture and in mice. DHQs inhibit the nucleotidyltransferases TENT4A/B, also called PAPD7/5, which play a role in cellular mRNA “quality control” and noncoding transcript metabolism and are necessary for efficient HBV and HAV RNA functions. However, their mechanism of action against HBV and HAV are distinct: while DHQs promote degradation of HBV mRNAs, they do not affect HAV RNA stability. Instead DHQs suppress HAV RNA synthesis. The selective sensitivity of viral over host transcripts to DHQs offered a new strategy of antiviral therapy with low risk for resistance. However, DHQ development has been slowed and even suspended because of neurotoxicity concerns in long- term animal studies. We therefore produced a family of hepatoselective HS-DHQs that use receptors enriched on hepatocytes to achieve a liver-selective distribution. Our lead HS-DHQs 2 and 3 have been shown to have nano-molar activities against HAV in cell culture and they target hepatocytes in culture and are enriched in the liver in mice. We have now synthesized a family of HS-DHQs to optimize their PK profiles. Our mouse studies suggest effective therapy for hepatitis A will require only brief antiviral therapy, and we propose that our HS-DHQs with less plasma and other tissue exposure will carry a low risk of neurotoxicity when used in this context. In this STTR Phase I application, we will perform lead optimization to advance HS-DHQs based not only on anti-HAV efficacy in tissue culture and PK study results, but also a neurotoxicity screen using an in vitro assay with primary rat neurons and in vivo distribution to neuronal tissues. The best HS- DHQs will be further studied for their efficacy in treating and preventing HAV infection in mice. HS-DHQs with the best antiviral, PK, and PD performance in murine models of HAV will then be advanced through preclinical studies in Phase II necessary to support a human clinical study.