New generation of long acting nucleos(t)ides and immune stimulant for treatment of chronic hepatitis B

新一代长效核苷和免疫兴奋剂治疗慢性乙型肝炎

• 批准号: 10589089
• 负责人: Benson Edagwa
• 金额: $ 61.12万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-10 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589089
• 关键词: AIDS prevention; Adherence; Anti-Retroviral Agents; Antiviral Agents; Biodistribution; Biological Availability; Bypass; Cells; Chromosomes; Chronic Hepatitis B; Clinical; Clinical Trials; Collaborations; Complex; Development; Dose; Drug Delivery Systems; Drug Formulations; Drug Interactions; Drug Kinetics; Ensure; Formulation; Frequencies; Generations; Goals; HIV-1; Half-Life; Hepatitis B; Hepatitis B Antiviral; Hepatitis B Infection; Hepatitis B Surface Antigens; Hepatitis Viruses; Hepatocyte; Human; Hydrophobicity; Immunity; Immunomodulators; Immunotherapy; In Vitro; Individual; Infection; Injectable; Innate Immune Response; Interferon Alfa-2a; Interferon alpha; Interferons; Intramuscular Injections; Kupffer Cells; Liver; Liver Fibrosis; Liver diseases; Macrophage; Malignant neoplasm of liver; Medicine; Modeling; Mus; Natural Immunity; Nebraska; Oral; Oral Administration; Parents; Patients; Pharmaceutical Preparations; Phenotype; Polymerase; Prevention; Prodrugs; Property; Protocols documentation; Protozoa; Recommendation; Regimen; Safety; Signal Pathway; Site; Suspensions; Technology; Tenofovir; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Treatment Protocols; Treatment outcome; Viral; Viral Physiology; Virus Diseases; Virus Replication; Vulnerable Populations; Water; adaptive immune response; alcohol abuser; analog; clinical translation; controlled release; drug action; drug efficacy; drug metabolism; efficacy study; end stage liver disease; entecavir; experience; forging; humanized mouse; immune modulating agents; immune stimulant; immunoregulation; improved; in vivo; in vivo Model; inhibitor; lipophilicity; manufacturing facility; nano; nanocrystal; nanoformulation; nanomedicine; nanoparticle; nitazoxanide; pharmacokinetics and pharmacodynamics; pill; prevent; response; side effect; substance abuser; uptake; viral DNA; viral liver disease

There is a global aim to reduce the burden of chronic hepatitis B (CHB) infection and prevent the development of HBV-associated end-stage liver disease and cancer. The improvement of existing therapeutics is expected to help achieve this goal. Specifically, the usage of once two-month injectable nucleos(t)ide analogs in combination with immunomodulating antiviral compounds instead of life-long daily pills has the strong potential to help to achieve a functional cure for CHB. To this end, we propose to transform water-soluble antiviral drugs, first-line drugs tenofovir (TFV) and entecavir (ETV), and immunomodulating drug tizoxanide (TIZ) into hydrophobic lipophilic crystalline prodrugs. We will formulate them as nanosuspensions suitable for intramuscular injection. The efficient optimization of physicochemical properties of nanocrystals is expected to improve their pharmacokinetics (PK) and pharmacodynamics (PD) profiles. This optimization will enhance uptake of the prodrug nanocrystals by liver macrophages and hepatocytes to ensure a slow release and sustained therapeutic drug concentrations at the site of hepatitis B viral replication. The treatment with long-acting TFV, ETV, and TIZ is expected to decrease dosing frequency, limit toxicity, and facilitate sustained viral suppression and treatment. A functional cure for HBV is expected to be achieved via multifactorial mechanisms, including inhibition of viral polymerase, prevention of cccDNA formation, and the clearance of HBV micro-chromosomes via stimulation of host innate immunity by TIZ. Thus, the overall objective of this proposal is to develop clinically translatable, long-acting, injectable, antiviral drug nanoformulations to increase adherence and enhance drug delivery to sites of persistent HBV infection, thereby facilitating sustained viral suppression and finite cure. To this end, three specific aims are proposed: Aim 1: Develop long-acting anti-HBV prodrug nanoformulations and evaluate the drug efficacy. Here, we will apply pronucleotide (ProTide) and a modified HepDirect prodrug technology to transform existing drugs into hydrophobic prodrugs suitable for formulation as nanosuspensions to achieve prolonged therapeutic active drug concentrations in hepatocyte. This is expected to improve drug biodistribution to infected hepatocytes without compromising drug potency and safety profile. The prodrug formulations will be screened in vitro in human macrophages as a potential drug depot and in infected hepatocytes as final targets. The anti-HBV activity of prodrug nanocrystals will be examined in vitro and in vivo using HBV-infected humanized mice. Aim 2: To develop long-acting TIZ nanoformulation and evaluate the mechanisms by which TIZ suppresses HBV replication in infected hepatocytes. Aim 3: To evaluate the synergistic efficacy of the selected long-acting TIZ and NUC formulations and evaluate the ability of this combination to eliminate HBV cccDNA from hepatocytes and significantly reduce the concentration of HBsAg.

全球旨在减轻慢性肝炎（CHB）感染的负担，并防止 与HBV相关的终末期肝病和癌症的发展。改善现有治疗剂 期望有助于实现这一目标。具体而言，使用曾经两个月可注射的核（T）IDE的使用 类似物与免疫调节的抗病毒化合物而不是终生的每日药具有 有助于实现CHB功能治疗的强大潜力。为此，我们建议转化水溶性 抗病毒药物，一线药物替诺福韦（TFV）和Entecavir（ETV）以及免疫调节药物Tizoxanide （TIZ）成疏水性亲脂性晶体前药。我们将它们作为适合 肌内注射。有效优化纳米晶体的物理化学特性 改善他们的药代动力学（PK）和药效学（PD）概况。这种优化将增强 通过肝巨噬细胞和肝细胞对前药纳米晶体的吸收，以确保缓慢释放和 丙型肝炎病毒复制部位的持续治疗药物浓度。 长效TFV，ETV和TIZ的治疗预计将降低剂量频率，极限毒性， 并促进持续的病毒抑制和治疗。预计将实现HBV的功能治疗 通过多因素机制，包括抑制病毒聚合酶，预防CCCDNA形成和 通过TIZ刺激宿主先天免疫，HBV微染色体清除。因此，整体 该建议的目的是开发可翻译，长效，可注射抗病毒药的目的 纳米制剂以增加依从性并增强药物递送到持续性HBV感染部位， 从而促进持续的病毒抑制和有限的治疗方法。为此，提出了三个具体目标： 目标1：开发长效抗HBV前药纳米制剂并评估药物疗效。在这里，我们会的 施用丙杜请转肽（摄影）和修改的肝前药技术，将现有药物转化为 疏水前药适用于作为纳米舒张的配方，以实现长时间的治疗活性 肝细胞中的药物浓度。预计这将改善药物生物分布来感染的肝细胞 没有损害药物效力和安全性。原始制剂将在体外筛选 人类巨噬细胞作为潜在的药物库，并在被感染的肝细胞中作为最终靶标。抗HBV 前药纳米晶体的活性将在体外和体内使用HBV感染的人源化小鼠进行检查。目的 2：开发长效TIZ纳米化并评估TIZ抑制HBV的机制 感染的肝细胞复制。目标3：评估选定的长效TIZ的协同功效 和NUC配方并评估该组合消除肝细胞中HBV CCCDNA的能力 并显着降低HBSAG的浓度。