Targeting endogenous sialidases for treatment of endotoxic shock

描述(申请人提供)：尽管抗生素的进步，脓毒症仍然是人类健康的主要挑战，因为在过去的二十年里，严重的脓毒症的存活率和发病率基本上没有变化。因此，开发新的治疗方法非常重要。我们最近报道了细菌唾液酸酶可能作为多菌败血症的治疗靶点。然而，由于大多数导致脓毒症的细菌不编码唾液酸酶，仅针对细菌唾液酸酶将不足以治疗脓毒症。为了将最初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作为治疗脓毒症的靶点。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-羟基神经氨酸(Neu5Gc2en)对致死性内毒素休克具有100%的保护作用。由于内毒素不含微生物唾液酸酶，因此抑制物必须针对宿主唾液酸酶(S)。此外，利用在造血细胞中定向突变了Neu1基因的小鼠，我们证明了NEU1在内毒素休克的严重性和对Neu5Gc2en的治疗反应中都发挥了关键作用。这些结果表明，NEU1是内毒素休克的潜在治疗靶点，内毒素休克是脓毒症的发病机制之一，目前的治疗在很大程度上对内毒素休克没有反应。基于这些令人兴奋的观察，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。我们的目标是确定一种先导化合物THA在治疗内毒素休克方面有效，毒性最小。

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.