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

基本信息

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
项目类别：
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

项目摘要

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。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 的功能然而，它们针对 HBV 和 HAV 的作用机制是不同的： DHQ 会促进 HBV mRNA 的降解，但不会影响 HAV RNA 的稳定性。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。 DHQ 提供了一种耐药风险较低的新抗病毒治疗策略。由于长期的神经毒性问题，开发已经放缓甚至暂停。因此，我们生产了一系列使用肝选择性 HS-DHQ 的药物。我们的主要 HS-DHQ 2 受体富集在肝细胞上，实现肝脏选择性分布。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，并且它们的目标是我们现在合成了一个家族的培养物中的肝细胞，并且在小鼠的肝脏中富集。我们的小鼠研究表明 HS-DHQ 可以有效治疗肝炎。 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本 STTR 中使用时，其他组织暴露的神经毒性风险较低。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。