Novel Peptide Immunomodulators for Treating Sepsis

治疗脓毒症的新型多肽免疫调节剂 脓毒症是一种由于宿主免疫调节失调而导致的危及生命的临床症状。 对感染的反应，这会导致多器官衰竭。约170万美国成年人患有脓毒症 每年导致住院和27万人死亡。在那些幸存下来的人中，近50% 脓毒症患者再次住院，六分之一的幸存者无法存活超过一年。脓毒症 其特征是菌血症增加，导致高系统炎症反应和 未能使免疫平衡正常化导致败血症休克5。治疗包括 针对细菌感染的抗生素和对目标器官的支持性护理。然而，没有 目前有针对和治疗高免疫反应的药物，这表明 是进行性脓毒症治疗的关键未得到满足的需求。ORAI1是一种质膜钙通道 这调节了一个基本的过程，即存储操作的钙离子进入(SOCE)。ORAI1/SOCE近端 在炎症信号转导和调节核因子-κB介导的转录和分泌前- 炎症反应。短腭肺鼻上皮克隆1(SPLunc1)是一种 分泌的天然防御蛋白。我们发现SPLUN1的S C端α6区域是一个特异的 Orai1的抑制剂。因此，SPLUN1/α6负性调节Orai1以降低SOCE和 发炎。因此，ELDEC计划使用α6肽模拟物来抑制Orai1 脓毒症时的炎症。Eldec已成功开发出SPLunc1的ELD607 完全优化大小的多肽模拟物，显著更有效和更具蛋白水解性 我们发现α6显著降低了Orai1/SOCE值， 随后的炎症反应与脓毒症和/或细菌性肺炎有关。我们的 初步数据表明，ELD607可减少金黄色葡萄球菌和肺炎链球菌引起的败血症。 小鼠肺炎模型中的铜绿假单胞菌。此外，用ELD607治疗的小鼠增加了 存活，表明ELD607没有免疫抑制作用。我们的数据还表明，ELD607 在脂多糖诱导的脓毒症模型中，降低血液中性粒细胞并改善体重。因此，我们的 研究表明，ELD607是一种新型的免疫调节剂，对脓毒症有效。 我们承认小鼠脓毒症模型的局限性。因此，为了更好地翻译我们的发现， 我们将评估ELD607作为一种治疗内毒素诱导的脓毒症患者免疫功能的方法 细胞和非人灵长类动物体内。我们将首先评价ELD607人血清的稳定性 败血症患者。然后，我们将评估ELD607‘S对脓毒症患者中性粒细胞的疗效 病人。然后，我们将在脂多糖诱导的脓毒症中验证ELD607‘S对非人类灵长类动物的疗效 为了研究ELD607对减少脓毒症疾病进展的影响。

Novel Peptide Immunomodulators for Treating Sepsis Sepsis is a life-threatening clinical condition which results from a dysregulation of host immune responses to infection, which leads to multi-organ failure. Sepsis occurs in ~1.7 million US adults annually resulting in hospitalization and 270,000 deaths. Of those that survive, nearly 50% of sepsis patients are re-hospitalized and one in six of survivors do not survive past one year. Sepsis is characterized by increased bacteremia resulting in hyper-systemic inflammatory responses and a failure to normalize immune homeostasis resulting in septic shock5. Treatment consists of antibiotics to target bacterial infections and supportive care for targeted organs. However, no drugs are currently available to target and treat the hyper immune response, indicating that there is critical unmet need for progressive sepsis therapies. Orai1 is a plasma membrane Ca2+ channel that regulates store operated Ca2+ entry (SOCE), a fundamental process. Orai1/SOCE is proximal in inflammatory signaling and regulates NF-κB-mediated transcription and secretion of pro- inflammatory responses. Short Palate LUng and Nasal epithelial Clone 1 (SPLUNC1) is a secreted innate defense protein. We found that SPLUNC1’s C-terminal α6 region is a specific inhibitor of Orai1. Thus, SPLUNC1/α6 negatively regulates Orai1 to reduce SOCE and inflammation. Eldec therefore plans to inhibit Orai1 using α6 peptidomimetics to inhibit inflammation during sepsis. Eldec has successfully developed ELD607, a SPLUNC1 peptidomimetic that is fully size- optimized, and significantly more potent and more proteolytically stable than SPLUNC1 α6. We have found that ELD607 significantly reduces Orai1/SOCE and subsequent inflammatory responses associated with sepsis and/or bacterial pneumonia. Our preliminary data demonstrate that ELD607 reduces sepsis caused by S. aureus and P. aeruginosa in murine pneumonia models. Additionally, mice treated with ELD607 had increased survival, suggesting that ELD607 is not immunosuppressive. Our data also indicate that ELD607 reduced blood neutrophilia and improved weight in an LPS-induced sepsis model. Thus, our studies demonstrate that ELD607 is a novel immunomodulator that is effective against sepsis. We acknowledge the limitations of murine sepsis models. Thus, to better translate our findings, we will evaluate ELD607 as a treatment for LPS-induced sepsis in human sepsis patient immune cells and in nonhuman primates. We will first evaluate the stability of ELD607 human serum from sepsis patients. We will then evaluate ELD607’s efficacy in human blood neutrophils of sepsis patients. We will then validate ELD607’s efficacy in nonhuman primates in an LPS-induced sepsis in order to study the impact of ELD607 on reducing sepsis disease progress.