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

开发 Waixenicin A 药效团作为新生儿缺氧性脑损伤的治疗干预措施

基本信息

批准号：
10577489
负责人：
Zhong-Ping Feng
金额：
$ 37.29万
依托单位：
BAYLOR UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577489
关键词：
ABCB1 gene Acute Address Adverse event Affinity Animal Model Asphyxia Behavioral Binding Biological Assay Birth Blood - brain barrier anatomy Brain Brain Hypoxia-Ischemia Brain Injuries Calcium Cause of Death Cell membrane Cell physiology Central Nervous System Diseases Cerebral Palsy Chemicals Child Chimeric Proteins Chronic Clinical Competence Cytochrome P450 Data Death Rate Derivation procedure Development Diagnosis Diagnostic Disease Dissociation Drug Kinetics Drug Targeting Effectiveness Electrophysiology (science)Elements Event Goals Hawaiian Healthcare Systems Hour Hypoxia Hypoxic Brain Damage Hypoxic-Ischemic Brain Injury In Vitro Infant Ion Channel Ischemia Lead Libraries Light Membrane Proteins Microsomes Modeling Molecular Probes Morbidity - disease rate Mus Natural Source Neonatal Nervous System Trauma Neurologic Neurons Neuropsychology Newborn Infant Outcome Oxygen Penetration Perinatal Perinatal Hypoxia Pharmaceutical Chemistry Phase Phosphotransferases Plasma Proteins Premature Infant Property Qualifying Recovery Rest Safety Slice Solubility Structure-Activity Relationship Survivors Testing Therapeutic Therapeutic Agents Therapeutic Intervention Time Validation Work adverse outcome analog aqueous blood-brain barrier penetration blood-brain barrier permeabilization clinical candidate coral deprivation disability drug development economic implication evidence base hypoxia neonatorum improved in vitro testing in vivo inhibitor innovation life time cost marine marine natural product mortality mouse model natural hypothermia neonatal hypoxic-ischemic brain injury neonatal mice neonate neuroprotection new therapeutic target novel therapeutic intervention pharmacologic pharmacophore pre-clinical prevent protective effect screening socioeconomics standard of care therapeutic candidate

项目摘要

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.

项目概要/摘要新生儿和围产期缺氧缺血性脑损伤（HIBI）是急性死亡和慢性死亡的主要原因。婴儿和儿童的神经系统发病率在足月婴儿中占 2%，而在足月婴儿中这一比例接近 60% 早产儿。 20% 至 50% 的新生儿窒息死亡。在幸存者中，高达 25% 的人表现出永久性脑瘫等神经心理障碍给美国医疗保健系统带来了终生成本估计为 115 亿美元。低温治疗是第一个基于证据的神经保护方法新生儿缺氧缺血性脑病（HIE）的治疗已成为临床护理标准（SOC）。尽管降低了死亡率和残疾率，但仍必须开始低温治疗 HIE 的 6 小时内，诊断窗口非常窄。在此时间范围内确诊的新生儿将接受治疗低温治疗3天。目前，大约一半接受低温治疗的 HIE 新生儿会出现不良反应对个人和社会经济产生影响的结果。显然，对充足的需求尚未得到满足超越当前 SOC 的针对 HIBI 的治疗干预。二价离子通道激酶融合蛋白 TRPM7 控制参与缺血事件的关键细胞过程，包括实验性 HIBI，以及是一个符合生物学原理且非常有前景的药物开发目标，特别是考虑到以下发现： waixenicin A (WaixA) 是一种高度选择性且有效的抑制剂。这提供了一个极好的起点开发 WaixA 的半合成衍生物，其药理学特性得到改善，可用于治疗对 HIBI 的干预。由于既定的 TRPM7的参与缺氧和WaixA HIBI 的有效性，我们假设半合成蜡A 衍生品保护对抗日美；那个半 WaixA 的合成类似物与 TRPM7 共价结合；并且，基于其出色的血脑预测阻隔性能，优化的 waixA 半合成类似物具有改善的理化性能，可用于作为针对 HIBI 的治疗先导化合物。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：依赖于我们各自核心专业知识和能力的互补方法：(1) 通过对分离的 WaixA (R61) 进行衍生化，对 WaixA 类似物进行合成优化； (2) 效力，通过药用半合成waixenicin衍生物的体外选择性、ADME和安全性筛选化学筛选级联并选择 3 个 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 种合格的半合成维克斯尼星衍生物进行治疗验证新生儿缺氧缺血性脑损伤 (HIBI) 体内（R61 和 R33）的研究，最终实现向 Blueprint 的过渡。