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.

抽象的 SARS-COV-2宿主响应与大范围免疫炎症有关 进化和组织损伤。我们正在开发一种创新的疗法BP-1002， 钝性炎症细胞因子并保护组织。 BP-1002有可能防止器官 不论病毒变体如何，COVID-19的伤害和死亡。 BP-1002是肾酶（RNLS） 激动剂 - 最近发现的秘密蛋白质，可促进细胞存活并下调 通过血浆钙钙ATPase信号传导通过信号传导的炎症反应， ATP2B4（PMCA4B）受体，并激活生长和存活途径（蛋白激酶B， jak/stat和MAP激酶）。该活性包含在20-40个氨基酸RNLS位置中。 由于RNLS是需要制造的大型蛋白质复合物，我们设计和开发了 BP-1002，一种36-AA RNLS（97.3％氨基酸身份），包含RNLS 活动网站。该RNLS激动剂是稳定的，可以使用化学合成易于制造。 初步数据表明，低血浆RNL与疾病严重程度相关 COVID-19患者；或急性肾脏损伤，心脏损伤和胰腺炎 19并发症。此外，BP-1002钝化炎症细胞因子的产生（IL6，TNFα和IL1β） 在人体血液中暴露于SARS-COV-2的S-和M蛋白质中；改善生存率 在模拟病毒疾病的小鼠模型（poly（i：c）或SARS-COV-2感染）中，有60％。 BP-1002 或重组RNL通过调节炎症减少细胞和组织损伤， 维护血管完整性和预防凋亡。另外，在鼠标中 炎症模型，单剂量的BP-1002具有持续6（静脉内）或10的活性 （皮下）小时。此外，小鼠的慢性剂量药物研究显示 与理想的治疗指数一致性。这些研究证实了BP-的强大潜力 1002作为COVD-19的新治疗方法。 BP-1002也可能单独使用或组合 与其他Covid-19疗法一起。测试的候选者是IL-6抑制剂，已显示 COVID-19治疗的各种好处。我们计划进一步的BP-1002概念评估证明， 单独或具有潜在的协同IL-6抑制作用，钝性细胞因子，防止 在几种小鼠互联19模型中的组织损伤和死亡。另外，我们将比较 输注30分钟后的药代动力学，将在患者中使用的给药途径 使用病毒小鼠模型在SC管理后进行剂量反应研究后的剂量反应研究。最后， 其他分析研究将允许为将来的生产设置规格。