Optimization of Novel Molecular Target-based Drugs for Arsenical Skin Injury

砷皮肤损伤新型分子靶点药物的优化

基本信息

批准号：
10023318
负责人：
Mohammad Athar
金额：
$ 74.1万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10023318
关键词：
Accidents Acids Acute Animal Model Anti-Inflammatory Agents Antidotes Antioxidants Arsenic Arsenicals Asia Attenuated Award Biological Biological Assay British Bulla Cell Death ChIP-seq Characteristics Chelating Agents Chemical Warfare Chemical Weapons Chemicals China Clinic Clinical Complex Cutaneous Cysteine Dangerousness Data Dermatology Development Dose Drug Formulations Event Exposure to FDA approved Family suidae Formulation Funding Generations Germany Health protection Human Human Rights Inflammation Inflammatory Response Injury Intervention Investigation Italy Japan Laboratories Lesion Maximum Tolerated Dose Mediating Miniature Swine Modeling Molecular Molecular Chaperones Molecular Target Mus Mustard Gas Outcome Oxides Pain Pathogenesis Pathway interactions Pharmaceutical Preparations Phosphorylation Poison Population Protective Agents Proteins Publishing Reactive Oxygen Species Records Reporting Research Risk Role Safety Scientist Security Seminal Signal Transduction Skin injury Syria System Therapeutic Therapeutic Agents Tissues Topical application Toxic effect Toxicology Translations USSR United States National Institutes of Health Validation Vesicants World War I World War II base chemical threat clinical candidate clinical translation design effective therapy endoplasmic reticulum stress experience inhibitor/antagonist lead optimization lewisite mouse model novel pre-clinical programs propellant protein folding protein misfolding response skin lesion small molecule therapeutic lead compound transcription factor transcriptome sequencing treatment strategy validation studies weapons web site

项目摘要

Arsenicals such as lewisite, diethylchloroarsine, diphenylchlorarsine, and diphenylcyanoarsine are extremely toxic chemicals that have been used in chemical warfare since World War I and continue to remain a threat to humans, who may be exposed through accidental or intentional mass population exposure. Topical exposure to these agents results in severe cutaneous blistering, inflammation and pain, and therapeutic strategies that safely and effectively attenuate this damage remain urgently needed. Such a strategy has long remained elusive in large part because the molecular mechanisms that underlie the cutaneous damage caused by arsenicals had not been identified. With our previous award, we developed murine and porcine models that, upon topical arsenical exposure, develop cutaneous lesions nearly identical to those that occur in humans. Employing these animal models, we identified a master regulatory signaling cascade underpinning the complex pathobiology of arsenicals. Mechanistically, the inflammatory responses, cell death, tissue disruption, and pain pathways induced by cutaneous arsenicals exposure are mediated by the induction of endoplasmic reticulum (ER) stress and reactive oxygen species generation and subsequent activation of unfolded protein response (UPR) signaling, particularly that involving the ATF4-eIF2α axis. Phosphorylated eIF2α, which we found to be upregulated after arsenicals exposure, blocks translation of most nascent proteins but upregulates the translation of the ATF4 transcription factor. RNA-Seq and CHIP-Seq data confirmed an unbiased role of ATF4 in the pathogenesis of the skin lesions and identified a unified role of ATF4-regulated proteins in this injury. Therefore, we investigated the therapeutic potential of the chemical chaperone 4-phenylbutyric acid (4-PBA), which has been shown to enhance protein folding and reduce ER stress; the antioxidant N-acetyl cysteine (NAC); and the inhibitor of eIF2α phosphorylation ISRIB. Each of these drugs was highly effective in restoring protein translation and diminishing inflammation, tissue disruption, and pain in our mouse model. Thus, we have validated the mechanism-based efficacy of these small molecule agents against cutaneous toxicity induced by arsenicals. 4-BPA and NAC are FDA approved, thus we propose to advance these findings through the lead optimization of 4-PBA and NAC delivered by topical administration after arsenicals exposure in our murine and porcine models. Specifically, we propose to determine the efficacy of the maximum tolerated dose, the window of efficacy, and the durability of response for these drugs, alone and in combination, in treating arsenicals-mediated cutaneous injury in mice (Aim 1); to develop various topical formulations of these drugs and assess the efficacy thereof against arsenicals-mediated cutaneous injury in mice (Aim 2); and to confirm the efficacy of the identified novel outstanding formulation in our porcine model of arsenicals-mediated cutaneous injury (Aim 3). These studies will drive the clinical translation of an antidote for the cutaneous toxicity of arsenicals, which may be further expedited as these drugs are already FDA approved.

诸如Lewisite，二乙基氯苯胺，二苯基氯氨基和二苯基糖苷的砷酸盐非常极端自第一次世界大战以来在化学战中使用的有毒化学物质，并继续对人类可能会因意外或故意的群众暴露而暴露。局部暴露对于这些代理商，会导致严重的皮肤发泡，创新和痛苦以及治疗策略安全有效地减弱这种损害仍然需要迫切需要。这种策略长期以来一直保持难以捉摸的很大程度上是因为分子机制是由尚未确定砷。有了我们以前的奖项，我们开发了鼠类和猪模型，局部砷暴露时，发育于皮肤病变几乎与人类发生的病变相同。使用这些动物模型，我们确定了一个基于该复合物的主管信号传导级联砷的病理学。从机械上讲，炎症反应，细胞死亡，组织破坏和疼痛皮肤砷暴露诱导的途径是通过诱导内质网介导的（ER）应力和活性氧的产生以及随后的展开蛋白质反应的激活（UPR）信号，特别是涉及ATF4-EIF2α轴的信号传导。磷酸化的EIF2α，我们发现这是砷暴露后上调，阻止了大多数新生蛋白的翻译，但上调了 ATF4转录因子的翻译。 RNA-seq和ChIP-Seq数据证实了ATF4的无偏作用在皮肤病变的发病机理中，并确定了ATF4调节蛋白在这种损伤中的统一作用。因此，我们研究了化学伴侣4-苯基丁酸（4-PBA）的治疗潜力，已显示可增强蛋白质折叠并减轻质网应激；抗氧化剂N-乙酰半胱氨酸（NAC）; EIF2α磷酸化ISRIB的抑制剂。这些药物中的每一个都在恢复中非常有效我们的小鼠模型中的蛋白质翻译和减少注射，组织破坏和疼痛。已经验证了这些小分子剂对皮肤毒性的基于机制的效率由砷诱导。 4-BPA和NAC已获得FDA批准，因此我们建议通过在我们鼠和猪模型。具体而言，我们建议确定最大耐受剂量的效率，效率的窗口以及这些药物的持久性，单独和组合的效率，治疗小鼠砷介导的皮肤损伤（AIM 1）；开发这些药物的各种局部配方并评估其针对小鼠中砷介导的皮肤损伤的效率（AIM 2）；并确认我们砷介导的猪模型中已确定的新型出色公式的效率皮肤伤害（AIM 3）。这些研究将推动皮肤解毒剂的临床翻译砷的毒性可能会进一步加快，因为这些药物已经获得FDA批准。