Targeting endogenous sialidases for treatment of endotoxic shock

靶向内源性唾液酸酶治疗内毒素休克

• 批准号: 8781212
• 负责人: Ping Qiu
• 金额: $ 20万
• 依托单位: ONCOIMMUNE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8781212
• 关键词: Antibiotics; Bacteria; Cells; Cessation of life; Endotoxic Shock; Endotoxins; Genes; Goals; Gram-Negative Bacteria; Health; Hematopoietic; Hospitalization; Human; Incidence; Infection; Lead; Leukocytes; Microbe; Mus; Mutation; N-glycolylneuraminic acid; Neuraminidase; Pathogenesis; Production; Reporting; Role; Sepsis; Septic Shock; Series; Severities; Specificity; Structural Models; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Toxicity Tests; Treatment Efficacy; base; cytokine; inhibitor/antagonist; macrophage; microbial; mortality; novel; novel therapeutic intervention; peripheral blood; public health relevance; response; therapeutic target

DESCRIPTION (provided by applicant): Despite the advance of antibiotics, sepsis remains a major challenge to human health as both survival and incidence of severe sepsis have been largely unchanged in the last two decades. It is therefore important to develop new therapeutic approaches. We have recently reported that bacterial sialidases may serve as therapeutic targets for polybacterial sepsis. However, since the majority of bacteria that cause sepsis do not encode sialidases, targeting bacterial sialidases alone would be insufficient for therapy of sepsis. In order to expand the original concept to infections by microbes that do not produce sialidases, we hereby hypothesize that host sialidases can also be targeted for the treatment of sepsis. In support of this notion, we observed that a novel sialidase inhibitor 2-deoxy-2,3-dehydro-N-glycolylneuraminic acid (Neu5Gc2en) conferred 100% protection against lethal endotoxic shock. Since endotoxin does not contain microbial sialidases, the inhibitor has to target the host sialidase(s). Furthermore, using mice with a targeted mutation of Neu1 gene among the hematopoietic cells, we demonstrated a critical role for NEU1 in both severity of endotoxic shock and in therapeutic response to Neu5Gc2en. These results demonstrate that NEU1 is a potential therapeutic target for endotoxic shock, which contributes to pathogenesis of sepsis and remains largely unresponsive to current therapy. Based on these exciting observations, we will compare therapeutic effect of a series of newly synthesized sialidase inhibitors for their activity and selectivity for NEU1. The goal is to identify a lead compound tha is effective in treating endotoxic shock with minimal toxicity.

描述（由申请人提供）：尽管抗生素取得了进步，但脓毒症仍然是人类健康的主要挑战，因为在过去二十年中，严重脓毒症的生存率和发病率在很大程度上没有变化。因此，开发新的治疗方法非常重要。我们最近报道细菌唾液酸酶可能作为多细菌脓毒症的治疗靶点。然而，由于大多数引起脓毒症的细菌不编码唾液酸酶，因此仅针对细菌唾液酸酶不足以治疗脓毒症。为了将原来的概念扩展到不产生唾液酸酶的微生物感染，我们在此假设宿主唾液酸酶也可以靶向治疗败血症。为了支持这一观点，我们观察到一种新型唾液酸酶抑制剂2-脱氧-2,3-脱氢- n -糖基神经氨酸（Neu5Gc2en）对致命的内毒素休克具有100%的保护作用。由于内毒素不含微生物唾液酸酶，因此抑制剂必须靶向宿主唾液酸酶。此外，利用造血细胞中Neu1基因靶向突变的小鼠，我们证明了Neu1在内毒素休克的严重程度和Neu5Gc2en的治疗反应中都起着关键作用。这些结果表明NEU1是内毒素休克的潜在治疗靶点，它有助于脓毒症的发病机制，并且对目前的治疗在很大程度上没有反应。基于这些令人兴奋的观察结果，我们将比较一系列新合成的唾液酸酶抑制剂对NEU1的活性和选择性的治疗效果。目的是确定一种先导化合物，有效治疗内源性休克，毒性最小。