A Hybrid PARP Inhibitor and Redox Catalyst for Lung Transplantation

用于肺移植的混合 PARP 抑制剂和氧化还原催化剂

基本信息

批准号：
8248350
负责人：
Garry John Southan
金额：
$ 24.95万
依托单位：
RADIKAL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-10 至 2014-08-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8248350
关键词：
Acute Address Adult Respiratory Distress Syndrome Animal Model Animals Apoptosis Attention Attenuated Autopsy Biological Assay Blinded Blood Blood Chemical Analysis Breathing Bronchoalveolar Lavage Cells Cessation of life Chairperson Chemistry Chlorine Clinical Complication Cytoprotective Agent DNA Damage DNA Repair Enzymes DNA Single Strand Break Dose Drug Delivery Systems Environmental air flow Excision Exhibits Experimental Models Free Radicals Genes Genetic Hematology Histologic Histology Histopathology Hospitalization Hybrids Hydrogen Peroxide Hydroxyl Radical In Situ In Vitro Infiltration Inflammatory Inhibitory Concentration 50 Injury Intercellular adhesion molecule 1 Interruption Investigation Ischemia Left lung Legal patent Length Life Lipid Peroxidation Long-Evans Rats Lung Lung Transplantation Lung diseases Macrophage Inflammatory Protein-1 Measures Mechanical ventilation Medical Membrane Modality Modeling Multiple Organ Failure Mus Necrosis Neutrophil Infiltration Nitrosation Nuclear Organ Organ Transplantation Orphan Drugs Outcome Oxidation-Reduction Oxygen P-Selectin Pathway interactions Permeability Peroxonitrite Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Placebo Control Plasma Pneumonia Poly(ADP-ribose) Polymerases Population Prevention Property Proteins Pulmonary Edema Randomized Rattus Relative (related person)Reperfusion Injury Reperfusion Therapy Residual state Respiratory Failure Resuscitation Rodent Model Serum Shunt Device Small Inducible Cytokine A3 Staging Stress Structure of parenchyma of lung Sulfhydryl Compounds Superoxides TNF gene Technology Testing Therapeutic Tissues Toxic effect Toxin Translating Translations Transplantation Vascular Permeabilities Zymosan base catalase catalyst clinically relevant drug market exhaustion follow-up graft failure hemodynamics in vivo in vivo Model indexing inhibitor/antagonist innovation lung injury lung ischemia medical complication mimetics mortality neurobehavioral neutrophil nitrosative stress novel oxidant stress prevent professor prophylactic prospective response small molecule treatment effect

项目摘要

DESCRIPTION (provided by applicant): Radikal Therapeutics (RTX) is developing a novel bifunctional small molecule, R-503, intended for the prevention of lung ischemia-reperfusion injury (LIRI) associated with orthotopic lung transplantation. LIRI results from an acute reperfusion-induced alteration in the synthesis of the free radical superoxide anion that is subsequently converted into powerful toxins, including peroxynitrite, hydrogen peroxide, and hydroxyl radical. These oxidizing and nitrosating species induce DNA single strand breaks that activate poly(ADP-ribose) polymerase (PARP), a nuclear DNA repair enzyme that in turn depletes its substrate NAD, resulting in an exhaustion of intracellular energetics, ATP depletion, and tissue necrosis. PARP activation also induces a widespread expresion of pro-inflammatory genes that contribute to vascular permeability, lung edema, neutrophil infiltration, pulmonary shunt, and respiratory failure. In experimental models of LIRI injury, pharmacologic inhibition of PARP potently reduces lung injury, but the extent of protection was not complete and its successful clinical translation is uncertain. We now propose a more thorough interruption of LIRI-induced tissue damage, exploiting the simultaneous and synergistic removal of upstream DNA-damaging oxidizing and nitrosating species plus downstream PARP inhibition. R-503 is formed from the covalent linkage of 2 moieties, each with demonstrated tissue protection: 1) a PARP inhibitor moiety, and 2) a thiol-rich dihydrolipoyl ("DHL") domain that acts as a broad-spectrum redox catalyst. The inclusion of the DHL moiety confers unique properties on R-503, allowing the molecule to shut down both PARP-dependent and PARP-independent pathways of redox stress. R-503 is a potent PARP inhibitor (IC50=20 nM), more cytoprotective than a monofunctional PARP inhibitor in vitro, and remarkably protective in vivo, as shown in murine LD100 models of zymosan-induced multiple organ failure and chlorine inhalational lung injury. Specific Aim: Establish the superiority and in vivo synergy of the bifunctional PARP inhibitor R-503 in an experimental rat model of LIRI. Prior to 90 min of unilateral lung ischemia and 4 h of reperfusion, rats will be treated with IV R-503, DHL, a monofunctional PARP inhibitor (INO-1001), or a combination of DHL and INO-1001. A sham animal will not undergo ischemia nor receive drug therapy. We expect that R-503 will exhibit superior efficacy, relative to treatment with INO-1001, DHL, and their combination, with respect to: 1) tissue damage (histology score, levels of neutrophil infiltration, lipid peroxidation, protein nitrosation, vascular permeability, PARP activation, and apoptosis) and arterial oxygenation; and 2) bronchoalveolar lavage markers of pulmonary injury (levels of neutrophil infiltration, concentrations of TNF-¿, MIP-1¿, and nuclear NF-?B). Such treatment effects are expected to translate into clinical endpoints in LIRI of decreased: 1) pulmonary shunt, 2) duration of mechanical ventilation, 3) length of hospitalization, and 4) all-cause 30 and 365 day mortality. PUBLIC HEALTH RELEVANCE: Ischemia-reperfusion injury is a major medical complication following lung transplantation and contributes to the high mortality in this population. At present there are no approved prophylactic measures. We are developing a novel drug that targets the basic mechanisms of this condition and will test this agent in a clinically-relevant animal model.

描述（由适用提供）：Radikal Therapeutics（RTX）正在开发一种新型的双功能小分子R-503，旨在预防与正统肺部移植相关的肺部缺血再灌注损伤（LIRI）。 LIRI results from an acute reperfusion-induced alteration in the synthesis of the free radical superoxide anion that is subsequently converted into powerful toxins, including peroxynitrite, hydrogen PARP activation also induces a widespread expression of pro-inflammatory genes that contribute to vascular permeability, lung Edema, neutrophil infiltration, pulmonary shunt, and respiratory failure.在LIRI损伤的实验模型中，PARP的药物抑制可能会减少肺损伤，但是保护程度尚未完成，并且其成功的临床翻译尚不确定。现在，我们提出对LIRI诱导的组织损伤的更彻底中断，利用了上游DNA受损的氧化和亚硝化物种以及下游PARP抑制的最简单和协同的去除。 R-503是由2个部分的共价连接形成的，每个连接都有显示的组织保护：1）PARP抑制剂部分，以及2）一个充当广谱型氧化还原催化剂的富含硫醇的二氢脂蛋白（“ DHL”）结构域。 DHL部分的包含在R-503上赋予了独特的特性，从而使该分子可以关闭氧化还原应力的PARP依赖性和与PARP无关的途径。 R-503是一种潜在的PARP抑制剂（IC50 = 20 nm），比单官能PARP抑制剂在体外更具细胞保护作用，并且在体内受到了极大的保护，如Zymosan诱导的鼠LD100模型中所示，Zymosan诱导的多器官衰竭和氯的意外肺损伤。具体目的：在LIRI的实验大鼠模型中，建立双功能PARP抑制剂R-503的超级和体内协同作用。在90分钟的单侧肺部缺血和4小时再灌注之前，将用IV R-503，DHL，单功能PARP抑制剂（INO-1001）或DHL和INO-1001的组合对大鼠进行治疗。假动物不会患缺血或接受药物治疗。我们希望R-503相对于INO-1001，DHL及其组合的治疗，相对于：1）组织损伤（组织学评分，中性粒细胞浸润水平，脂质过氧化，蛋白硝基化，血管渗透性，PARP活化和脂肪氧化）和AREREXYGENTION; 2）肺损伤的支气管肺泡灌洗标记物（中性粒细胞浸润水平，TNF-®浓度，MIP-1？和核NF-？b）。预计这种治疗效果将转化为改进的LIRI的临床终点：1）肺管，2）机械通气持续时间，3）住院时间和4）全因30和365天死亡率。公共卫生相关性：缺血 - 重新灌注损伤是肺移植后的主要医学并发症，并导致该人群的高死亡率。目前尚无批准的预防措施。我们正在开发一种针对这种疾病的基本机制的新型药物，并将在临床上相关的动物模型中测试该药物。