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

用于治疗和预防甲型肝炎病毒 (HAV) 感染的肝选择性二氢喹嗪酮 (HS-DHQ) 分子

• 批准号: 10698516
• 负责人: Yanming Du
• 金额: $ 30万
• 依托单位: HARLINGENE LIFE SCIENCES LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698516
• 关键词: Ablation; Acids; Acute Hepatitis; Afferent Neurons; Animals; Antiviral Agents; Antiviral Therapy; Binding Proteins; Biochemical; Biological Assay; Biological Sciences; Blood; Brain; Caco-2 Cells; Categories; Cell Culture Techniques; Cell Line; Cellular Assay; Central Nervous System; Cessation of life; Chemoprevention; Clinical Research; Complex; Data; Developing Countries; Development; Disease; Disease Outbreaks; Dose; Drug or chemical Tissue Distribution; Enteral; Exposure to; Family; Hepatitis A; Hepatitis A Virus; Hepatitis B; Hepatitis B Antiviral; Hepatitis B Therapy; Hepatitis B Virus; Hepatocyte; Hospitalization; Human; In Vitro; Infection; Innate Immune Response; Integration Host Factors; Lead; Life; Liver; Messenger RNA; Metabolic; Metabolism; Microsomes; Mus; National Institute of Allergy and Infectious Disease; Neurons; Oral; Organ; Patients; Performance; Peripheral Nervous System; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Prevention; Public Health; Quality Control; RNA Stability; RNA Viruses; RNA chemical synthesis; Rattus; Resistance; Risk; Safety; Sanitation; Scientist; Serum; Small Business Technology Transfer Research; Spinal Ganglia; Stream; Structure; Therapeutic; Tissues; Toxic effect; Transcript; United States; Untranslated RNA; Vaccines; Viral; Viral Physiology; Viral hepatitis; Virus; Virus Diseases; Virus Replication; Work; acute liver injury; adaptive immune response; anti-hepatitis B; biodefense; clinical development; cytotoxicity; effective therapy; effectiveness evaluation; efficacy evaluation; hepatitis A virus antibodies; human model; improved; in vitro Assay; in vivo; lead candidate; lead optimization; liver inflammation; liver injury; liver transplantation; meter; monolayer; mouse model; nanomolar; neurite growth; neurotoxicity; novel; nucleotidyltransferase; pathogen; preclinical study; prevent; receptor; relapse prevention; scale up; sciatic nerve; tissue culture; transmission process; treatment duration; uptake; viral RNA

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.

肝选择性二氢喹啉酮（HS-HS-DHQ）分子进行治疗和预防 肝炎病毒感染 抽象的 这是I阶段的建议，旨在开发Harlingene的肝二氢喹啉酮（HS-- DHQS）用于治疗和预防肝炎病毒（HAV）感染。这将是第一个 治疗HAV感染的抗病毒疗法，该疗法是预防疾病的目的地疫苗 每年在美国DHQ中，成千上万的住院和许多死亡人数。 Roche化合物RG7834已被证明是丙型肝炎病毒（HBV）的有效抗病毒药 HBV正在开发许多小型和主要的药物 公司。我们正在开发DHQ，以治疗和预防肝炎 答：我们已经显示DHQ在细胞培养和小鼠中对HAV具有很高的活性。 DHQ抑制 核苷酸转移酶Tent4a/b，也称为PAPD7/5，在细胞mRNA中起作用 “质量控制”和非编码成绩单代谢，对于有效的HBV和 HAV RNA功能。但是，他们针对HBV和HAV的作用机制是不同的：而 DHQ促进了HBV mRNA的降解，它们不会影响HAV RNA稳定性。而不是DHQ 抑制HAV RNA合成。病毒对宿主转录本的选择性敏感性 提供了一种新的抗病毒治疗策略，其抵抗风险较低。但是，DHQ 由于长期存在神经毒性问题，开发已经放缓甚至暂停 术语动物研究。因此，我们生产了一个使用的肝选择HS-DHQ家族 富含肝细胞的接收器以实现肝选择性分布。我们的LEAD HS-DHQS 2 并且3已显示3个在细胞培养中具有针对HAV的纳米摩尔活性，它们靶向 培养中的肝细胞，并在小鼠的肝脏中富集。我们现在综合了一个家庭 HS-DHQ可以优化其PK配置文件。我们的小鼠研究建议有效治疗肝炎 A将仅需要简短的抗病毒疗法，我们建议我们的血浆较少的HS-DHQ和 在这种情况下，其他组织暴露会带来较低的神经毒性风险。在这个sttr中 第一阶段应用，我们将执行铅优化，以推进基于HS-DHQS 抗HAV在组织培养和PK研究结果中的抗HAV效率，但也使用神经毒性筛选 原发性大鼠神经元和体内分布到神经元组织的体外评估。最好的HS- DHQ将进一步研究其在治疗和预防小鼠HAV感染方面的效率。 HS-DHQS具有最佳的抗病毒，PK和PD性能的HS-DHQ，然后将是HAV的模型 通过在支持人类临床研究所需的II期临床前研究中进行的。