Development of the waixenicin A pharmacophore as a therapeutic intervention for neonatal hypoxic brain injury

项目总结/摘要 新生儿和围产期缺氧缺血性脑损伤（HIBI）是急性死亡和慢性脑损伤的主要原因。 婴儿和儿童的神经系统疾病发生在2%的足月婴儿中， 早产儿20%到50%的窒息新生儿死亡。在幸存者中，高达25%的人表现出永久性的 神经心理障碍，如脑瘫，产生终身成本，美国医疗保健系统， 估计为115亿美元。治疗性低温是第一个基于证据的神经保护 治疗新生儿缺氧缺血性脑病（HIE），并已成为临床护理标准 （SOC）。尽管降低了死亡和残疾的综合率，但必须开始治疗性低温 这是一个非常狭窄的诊断窗口。在这一时间范围内诊断的新生儿得到治疗， 体温过低3天。目前，约有一半的低血糖治疗的HIE新生儿出现不良反应， 结果与个人和社会经济的影响。显然，需要充分的 二价离子通道-激酶融合蛋白 TRPM 7控制参与缺血事件的关键细胞过程，包括实验性HIBI， 是药物开发的生物学逻辑和非常有前途的靶点，特别是鉴于发现 一种高度选择性和有效的抑制剂，Waixenicin A（WaixA）。这是一个很好的起点， 开发具有改善的药理学特性的WaixA的半合成衍生物， 干预HIBI。 由于建立了 TRPM的参与7 在缺氧和WaixA中 在HIBI中，我们 假设半- 合成乙酸乙酯 衍生品保护 而在这场半决赛中， WaixA的合成类似物与TRPM 7共价结合;并且，基于其出色的预测血脑- 阻隔性能，具有改善的理化性能的优化的waixA半合成类似物可以用作 作为治疗HIBI的先导药物 为了解决上述问题，我们的跨学科IGNITE团队建议采用以下组合： 基于我们各自的核心专业知识和能力的互补方法：（1）半 通过所提出的分离的WaixA（R61）的衍生化对WaixA类似物进行合成优化;（2）效力， 体外半合成怀塞霉素衍生物的选择性、ADME和安全性筛选 化学筛选级联和选择3种WaixA类似物作为体内工作的先导化合物（R61）;（3） 在已建立的小鼠模型中对这3种合格的半合成怀塞霉素衍生物进行治疗验证 新生儿缺氧缺血性脑损伤（HIBI）在体内（R61和R33），ulitabine使过渡到蓝图。

PROJECT SUMMARY/ABSTRACT Neonatal and perinatal hypoxic-ischemic brain injury (HIBI) is a major cause of acute mortality and chronic neurological morbidity in infants and children occuring in 2% of full-term infants and approaches 60% in premature infants. 20% to 50% of asphyxiated newborns die. Among the survivors, up to 25% show permanent neuropsychological handicaps such as cerebral palsy, generating lifetime costs to the US healthcare system at an estimated $11.5 billion USD. Therapeutic hypothermia was the first evidence-based neuroprotective therapy for neonates with hypoxic-ischemic encephalopathy (HIE) and has become the clinical standard of care (SOC). Despite reducing the combined rate of death and disability, therapeutic hypothermia has to be initaited within 6 hours of HIE, a very narrow diagnostic window. Neonates diagnosed within this time frame are treated with hypothermia for 3 days. Currently about half of hypothermia-treated HIE neonates experience adverse outcomes with personal and socioeconomic implications. Clearly, there is an unmet need for adequate therapeutic interventions against HIBI beyond current SOC. The divalent ion channel-kinase fusion protein TRPM7 controls critical cellular processes involved in ischemic events, including experimental HIBI, and is a biologically logical and highly promising target for drug development, particularly in light of the discovery of a highly selective and potent inhibitor, waixenicin A (WaixA). This provides an excellent starting point to develop semi-synthetic derivatives of WaixA with improved pharmacological properties towards therapeutic intervention in HIBI. Due to the established involvement of TRPM7 in hypoxia and WaixA effectiveness in HIBI, we hypothesize that semi- synthetic waixA derivatives protect against HIBI; that semi- synthetic analogs of WaixA covalently bind to TRPM7; and that, based on its excellent predicted blood-brain- barrier properties, optimized semi-synthetic analogs of waixA with improved physiochemical properties can serve as therapeutic leads against HIBI. To address the above, our interdisciplinary IGNITE team proposes to employ a combination of complementary approaches that rest on our respective core expertises and competencies: (1) Semi- synthetic optimization of WaixA analogs through proposed derivatization of isolated WaixA (R61); (2) Potency, selectivity, ADME and safety screens of semi-synthetic waixenicin derivatives in vitro through a Medicinal Chemistry Screening Cascade and selection of 3 WaixA analogs as lead compounds for in vivo work (R61); (3) Therapeutic validation of these 3 qualifying semi-synthetic waixenicin derivatives in an established mouse model of neonatal hypoxic-ischemic brain injury (HIBI) in vivo (R61 and R33) to ulitmately enable transition to Blueprint.