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.

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 抽象的 这是开发 Harlingene 的肝选择性二氢喹啉酮 (HS- DHQ）用于治疗和预防甲型肝炎病毒（HAV）感染。这将是第一个 抗病毒疗法治疗 HAV 感染，尽管有疫苗可以预防疾病，但 HAV 感染仍会导致 美国卫生总部每年有数千人住院治疗，许多人死亡，例如 罗氏化合物 RG7834 已被证明是治疗乙型肝炎病毒 (HBV) 的有效抗病毒药物 许多小型和大型制药公司都在针对 HBV 进行开发 公司。我们正在率先开发用于治疗和预防肝炎的 DHQ 答：我们已经证明 DHQ 在细胞培养物和小鼠体内对 HAV 具有高度活性。 DHQ 抑制 核苷酸转移酶 TENT4A/B，也称为 PAPD7/5，在细胞 mRNA 中发挥作用 “质量控制”和非编码转录代谢对于有效的 HBV 和 HAV RNA 功能。然而，它们针对 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。取而代之的是 DHQ 抑制 HAV RNA 合成。病毒相对于宿主转录本对 DHQ 的选择性敏感性 提供了一种低耐药风险的抗病毒治疗新策略。然而，DHQ 由于长期的神经毒性问题，开发已经放缓甚至暂停。 术语动物研究。因此，我们生产了一系列肝选择性 HS-DHQ，它们使用 受体富集在肝细胞上以实现肝脏选择性分布。我们的领导 HS-DHQ 2 和 3 种已被证明在细胞培养物中具有纳摩尔级的抗 HAV 活性，并且它们的目标是 培养物中的肝细胞在小鼠肝脏中富集。我们现在合成了一个家族 HS-DHQ 优化其 PK 配置文件。我们的小鼠研究表明肝炎的有效治疗 A 只需要短暂的抗病毒治疗，我们建议我们的 HS-DHQ 具有较少的血浆和 在这种情况下使用其他组织暴露时，神经毒性的风险较低。在这个STTR中 第一阶段的应用，我们将进行先导优化以推进 HS-DHQ，不仅基于 组织培养和 PK 研究结果中的抗 HAV 功效，以及使用 原代大鼠神经元的体外测定和神经元组织的体内分布。最好的HS- 将进一步研究 DHQ 在治疗和预防小鼠 HAV 感染方面的功效。 然后将在 HAV 小鼠模型中具有最佳抗病毒、PK 和 PD 性能的 HS-DHQ 通过支持人体临床研究所需的第二阶段临床前研究取得进展。