New target and new therapy for severe Covid-19 and viral hyperinflammation damage: renalase and renalase agonists

严重Covid-19和病毒性过度炎症损伤的新靶点和新疗法：肾酶和肾酶激动剂

• 批准号: 10759030
• 负责人: BARRY A BERKOWITZ
• 金额: $ 30万
• 依托单位: BESSOR PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759030
• 关键词: 2019-nCoV; Active Sites; Acute; Adrenal Cortex Hormones; Agonist; Amino Acids; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Biological Assay; Blood; Blood Vessels; Body Weight decreased; COVID-19; COVID-19 complications; COVID-19 morbidity; COVID-19 mortality; COVID-19 patient; COVID-19 severity; COVID-19 therapeutics; COVID-19 treatment; Cell Death; Cell Survival; Cessation of life; Chronic; Data; Dose; Dose Limiting; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Equilibrium; Evaluation; Exposure to; Freezing; Future; Growth; Health; Heart Injuries; High Pressure Liquid Chromatography; Histopathology; Hospitalization; Hour; Human; IL-6 inhibitor; IL6 gene; Immune response; Immunologics; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Infusion procedures; Injury; Injury to Kidney; Integration Host Factors; Interleukin-1 beta; Interleukin-6; Intravenous; Intravenous infusion procedures; Kidney; Length; Lung; Measurement; Mitogen-Activated Protein Kinases; Modeling; Mus; Onset of illness; PMCA1 protein; Pancreatitis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacology Study; Plasma; Poly I-C; Pre-Clinical Model; Prevention; Production; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Rattus; Recombinants; Rodent; Route; SARS-CoV-2 immune response; SARS-CoV-2 infection; Severities; Severity of illness; Shapes; Signal Transduction; Site; Spanish flu; Specific qualifier value; TNF gene; Technology; Temperature; Testing; Therapeutic; Therapeutic Index; Therapeutic Uses; Time; Tissues; Toxic effect; UV Radiation Exposure; Vaccines; Variant; Viral; Viral Load result; Virus; Virus Diseases; cell injury; chemical synthesis; cytokine; cytokine release syndrome; design; humanized mouse; improved; in vivo; innovation; kidney cell; manufacture; mortality; mouse model; multiple myeloma M Protein; new therapeutic target; novel; novel therapeutics; organ injury; pre-clinical; preservation; prevent; protein complex; receptor; response; secretory protein; severe COVID-19; side effect; subcutaneous; synergism; therapeutically effective; tissue injury; viral pandemic; welfare

Abstract The SARS-CoV-2 host response is associated with wide-ranging immuno-inflammatory derangements and tissue injury. We are developing an innovative therapeutic, BP-1002, to both blunt inflammatory cytokines and protect tissues. BP-1002 has the potential to prevent organ injury and deaths from COVID-19, regardless of viral variants. BP-1002, is a renalase (RNLS) agonist - a recently discovered secretory protein that promotes cell survival and downregulates the inflammatory response by signaling through the plasma-membrane calcium-ATPase, ATP2B4 (PMCA4b) receptor, and activating growth and survival pathways (protein kinase B, JAK/STAT, and MAP kinase). This activity is contained in a 20-40 amino acid RNLS site. Because RNLS is a large protein complex requiring manufacturing, we designed and developed BP-1002, a proprietary 36−aa RNLS-based (97.3 % amino acid identity) that contains the RNLS activity site. This RNLS agonist is stable and easily manufactured using chemical synthesis. Preliminary data show that low plasma RNLS correlates with disease severity hospitalized COVID-19 patients; or in acute renal injury, cardiac injury, and pancreatitis, which are COVID- 19 complications. Also, BP-1002 blunted inflammatory cytokine production (IL6, TNFα and IL1β) in human blood exposed ex vivo to the S- and M-proteins of SARS-CoV-2; improved survival by 60% in mouse models of simulated viral disease (poly(I:C) or SARS-CoV-2 infection). BP-1002 or recombinant RNLS reduced cell and tissue injury through modulation of inflammation, preservation of vascular integrity, and apoptosis prevention. Additionally, in a mouse inflammation model, single doses of BP-1002 had activity lasting 6 (intravenous) or 10 (subcutaneous) hours. Further, chronic-dosing pharmacology studies in mice show a profile consistent with a desirable therapeutic index. These studies confirm the strong potential for BP- 1002 as a new therapeutic for COVD-19. BP-1002 may also be useful alone or in combination with other COVID-19 therapies. A candidate for testing is IL-6 inhibitors, which have shown varied benefits for COVID-19 therapy. We plan further proof of concept evaluation of BP-1002, alone or with potentially synergistic IL-6 inhibition, to blunt inflammatory cytokines, prevent tissue damage and death in several mouse COVID-19 models. In addition, we will compare the pharmacokinetics after 30-min infusion, the route of administration that will be used in patients, with those after a dose-response studies after SC admin using a viral mouse model. Lastly, additional analytical studies will allow specifications to be set for future production.

摘要 SARS-CoV-2宿主反应与广泛的免疫炎症有关 排列紊乱和组织损伤。我们正在开发一种创新的疗法BP-1002，以 钝化炎性细胞因子，保护组织。BP-1002有可能预防器官 新冠肺炎造成的伤亡，而不考虑病毒变体。BP-1002是一种肾酶(RNLS) 激动剂--一种新近发现的促进细胞存活和下调表达的分泌性蛋白质 通过质膜钙-ATPase传递信号的炎症反应， ATP2B4(PMCA4b)受体和激活生长和生存途径(蛋白激酶B， JAK/STAT和MAP激酶)。该活性包含在20-40个氨基酸的RNLS位点上。 因为RNLS是一个需要制造的大型蛋白质复合体，所以我们设计和开发了 BP-1002，一种专有的36−AA RNLS(97.3%的氨基酸同一性)，包含RNLS 活动地点。这种RNLS激动剂很稳定，很容易用化学合成的方法制造。 初步数据显示，低血浆RNLS与住院的疾病严重程度相关 新冠肺炎患者；或急性肾损伤、心脏损伤和胰腺炎，这些都是冠状病毒感染- 并发症19例。BP-1002还抑制炎性细胞因子的产生(IL-6、肿瘤坏死因子α和IL-1β)。 在体外暴露于SARS-CoV-2 S和M蛋白的人血中；通过 在模拟病毒病(Poly(I：C)或SARS-CoV-2感染)小鼠模型中有60%。BP-1002 或重组RNLS通过调节炎症减少细胞和组织损伤， 保护血管完整性，防止细胞凋亡。此外，在鼠标中 炎症模型，单剂BP-1002的活性持续6(静脉)或10 (皮下)小时数。此外，在小鼠身上进行的慢性给药药理学研究表明， 符合理想的治疗指标。这些研究证实了BP的强大潜力- 1002作为治疗COVD-19的新疗法。BP-1002也可以单独使用或组合使用 配合其他新冠肺炎疗法。一个测试的候选药物是IL-6抑制剂，它已经表明 新冠肺炎的好处多种多样。我们计划对BP-1002进行进一步的概念验证评估， 单独或与潜在协同抑制IL-6，以钝化炎性细胞因子，防止 几种新冠肺炎小鼠模型的组织损伤和死亡。此外，我们还将比较 输液30分钟后的药代动力学，患者将使用的给药途径， 与那些在SC给药后进行剂量反应研究的小鼠采用病毒模型。最后， 更多的分析研究将允许为未来的生产设定规格。