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

摘要 SARS-CoV-2宿主反应与广泛的免疫炎症反应有关。 紊乱和组织损伤。我们正在开发一种创新的治疗，BP-1002， 抑制炎性细胞因子并保护组织。BP-1002有可能阻止器官 COVID-19造成的伤害和死亡，无论病毒变异如何。BP-1002是一种肾酶（RNLS） 激动剂-最近发现的一种分泌蛋白，可促进细胞存活并下调 通过质膜钙-ATP酶的信号传导的炎症反应， ATP 2 B4（PMCA 4 B）受体，并激活生长和存活途径（蛋白激酶B， JAK/STAT和MAP激酶）。这种活性包含在20-40个氨基酸的RNLS位点中。 由于RNLS是一种需要制造的大型蛋白质复合物，我们设计并开发了 BP-1002，一种基于36−aa RNLS的专利（97.3%氨基酸同一性），含有RNLS 活动现场。这种RNLS激动剂是稳定的，并且容易使用化学合成来制造。 初步数据显示，低血浆RNLS与住院的疾病严重程度相关 COVID-19患者;或急性肾损伤、心脏损伤和胰腺炎，这些都是COVID-19患者。 19并发症此外，BP-1002减弱了炎症细胞因子（IL 6、TNFα和IL 1 β）的产生。 在离体暴露于SARS-CoV-2的S-和M-蛋白的人血液中;通过 在模拟病毒性疾病（poly（I：C）或SARS-CoV-2感染）的小鼠模型中为60%。公司简介 或重组RNLS通过调节炎症减少细胞和组织损伤， 维持血管完整性和防止细胞凋亡。此外，在小鼠中， 在炎症模型中，BP-1002单次给药的活性持续6（静脉内）或10 （皮下）小时。此外，小鼠长期给药药理学研究显示， 与理想的治疗指数一致。这些研究证实了BP的强大潜力- 1002作为COVD-19的新治疗剂。BP-1002也可单独或组合使用 与其他COVID-19治疗方法。测试的候选者是IL-6抑制剂，其已经显示出 COVID-19治疗的各种益处。我们计划对BP-1002进行进一步的概念验证评估， 单独或与潜在的协同IL-6抑制一起，以钝化炎性细胞因子，预防 几种小鼠COVID-19模型的组织损伤和死亡。此外，我们将比较 30分钟输注后的药代动力学，将用于患者的给药途径， 与使用病毒小鼠模型SC给药后的剂量反应研究后的结果一致。最后， 进一步的分析研究将使我们能够为今后的生产确定规格。

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.