Synthetic Lung Surfactant Optimized for Biomedical Application

针对生物医学应用优化的合成肺表面活性剂

基本信息

批准号：
7780035
负责人：
FRANCISKUS JOHANNES WALTHER
金额：
$ 32.63万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7780035
关键词：
Acute Acute Lung Injury Adult Adult Respiratory Distress Syndrome Affect Albumins Alveolar Amino Acid Substitution Amino Acids Animals Binding Blood Vessels Blood capillaries Bronchoalveolar Lavage Burn Trauma C-terminal Charge Chemical Surfactants Child Childhood Circular Dichroism Clinical Computer Simulation DNA Insertion Elements Data Disease Drug Formulations Edema Engineering Environmental air flow Extravasation Family Fibrinogen Film Free Radicals Functional disorder Gases Generations Histology Hypochlorous Acid Inflammation Laboratories Lecithin Life Lipase Lipid Binding Lipids Lipopolysaccharides Lung Lung diseases LytA enzyme Mass Spectrum Analysis Measures Mechanics Methods Monitor N-terminal Nitrites Nonesterified Fatty Acids Oleic Acids Oryctolagus cuniculus Oxidative Stress Patients Peptides Phosphatidyl glycerol Phosphatidylglycerols Phospholipase Phospholipase A2 Plasma Proteins Pneumonia Post-Translational Protein Processing Premature Infant Preparation Property Proteins Pulmonary Surfactant-Associated Protein B Pulmonary Surfactants Quality Control Reactive Oxygen Species Reproducibility Resistance Respiratory physiology Secondary to Sepsis Serum Spectroscopy, Fourier Transform Infrared Stomach Structure Surface Testing analog animal disease transmission base capillary cost crosslink design effective therapy improved in vivo inhibitor/antagonist interstitial intravenous administration large scale production novel phosphonolipids prevent research study respiratory distress syndrome restoration surfactant synthetic peptide

项目摘要

DESCRIPTION (provided by applicant): Animal-derived surfactant preparations are highly effective in preventing and treating respiratory distress syndrome (RDS) in premature infants, but not in pediatric and adult patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). Effective therapy for ALI/ARDS will probably require synthetic surfactant with maximal surface activity and the ability to resist surfactant inhibition due to vascular leakage and acute inflammation. Such synthetic preparations offer the advantages of large-scale production, compositional reproducibility, easier quality control, stability with a long shelf-life, no transmission of animal disease, and lower costs. Synthetic surfactants also allow the use of novel protein and lipid components that may be more inhibition-resistant and possess biophysical properties that outperform native surfactant formulations than are presently available. Our laboratory has designed, synthesized, and characterized several highly-active analogs of surfactant protein B (SP-B), such as "Mini-B" (i.e., cross-linked construct of the N- and C-terminal domains of SP-B) and "Super Mini-B" (i.e., Mini-B with an insertion sequence at the N-terminus), and observed that Super-Mini-B further enhances the surface activity of synthetic surfactant preparations over that seen with native SP-B proteins. Mixing these SP-B analogs in non-toxic phospholipase-resistant lipids, i.e. phosphonolipid analogs of dipalmitoyl phosphatidylcholine (DPPC) and phosphatidylglycerol (PG), will promote inhibition resistance. The specific aims of this proposal are to (1) re-engineer, synthesize and characterize novel synthetic SP-B analogs designed to have high lipid-binding, surface activity and resistance to inhibition and oxidative stress in (phospholipase-resistant) lipid mixtures, and (2) define the in vivo efficacy of synthetic surfactants in rabbits with oleic acid- or lipopolysaccharide (LPS)-induced acute lung injury. We hypothesize that additional re-engineering of Mini-B and Super Mini-B, based on using discrete amino acid substitutions, will maximize their respective lipid binding and surface activity, and also increase their resistance to inhibition and oxidative stress. Formulation of these re-engineered SP-B analogs in phospholipase-resistant lipid mixtures may deliver a synthetic surfactant preparation uniquely able to treat ALI/ARDS. PROJECT NARRATIVE. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening respiratory diseases, which affect children and adults with sepsis, pneumonia, gastric aspiration, burns, trauma, and other acute illnesses. Survival depends on assisted ventilation, treatment of the underlying disease, and reversal of surfactant inhibition in the lung. Re-engineering of the essential surfactant protein B and the predominant lipids to enhance resistance to inhibition and oxidative stress may deliver a synthetic surfactant preparation uniquely able to treat ALI/ARDS.

描述（申请人提供）：动物源性表面活性剂制剂对于预防和治疗早产儿呼吸窘迫综合征（RDS）非常有效，但对于患有急性肺损伤（ALI）和急性呼吸窘迫综合征的儿童和成人患者无效。 ARDS）。 ALI/ARDS 的有效治疗可能需要具有最大表面活性的合成表面活性剂，并且能够抵抗由于血管渗漏和急性炎症而导致的表面活性剂抑制。此类合成制剂具有大规模生产、成分重现性好、质量控制更容易、稳定性好、保质期长、不传播动物疾病和成本较低等优点。合成表面活性剂还允许使用新的蛋白质和脂质成分，这些成分可能更具抑制性，并且具有比目前可用的天然表面活性剂配方更好的生物物理特性。我们的实验室设计、合成并表征了表面活性剂蛋白 B (SP-B) 的几种高活性类似物，例如“Mini-B”（即 SP-B 的 N 端和 C 端结构域的交联结构） B) 和“Super Mini-B”（即 N 末端有插入序列的 Mini-B），并观察到 Super-Mini-B 比天然 SP-B 进一步增强了合成表面活性剂制剂的表面活性。 B蛋白。将这些 SP-B 类似物混合在无毒的磷脂酶抗性脂质中，即二棕榈酰磷脂酰胆碱 (DPPC) 和磷脂酰甘油 (PG) 的磷脂类似物，将促进抑制抗性。该提案的具体目标是（1）重新设计、合成和表征新型合成 SP-B 类似物，其设计具有高脂质结合性、表面活性以及对（磷脂酶抗性）脂质混合物中的抑制和氧化应激的抵抗力， (2) 确定合成表面活性剂对油酸或脂多糖 (LPS) 诱导的急性肺损伤兔子的体内功效。我们假设，基于使用离散氨基酸取代对 Mini-B 和 Super Mini-B 进行额外的重新设计，将最大限度地提高它们各自的脂质结合和表面活性，并增加它们对抑制和氧化应激的抵抗力。这些重新设计的 SP-B 类似物在磷脂酶抗性脂质混合物中的配方可能会提供一种独特的能够治疗 ALI/ARDS 的合成表面活性剂制剂。项目叙述。急性肺损伤 (ALI) 和急性呼吸窘迫综合征 (ARDS) 是危及生命的呼吸系统疾病，影响儿童和成人，导致败血症、肺炎、胃误吸、烧伤、创伤和其他急性疾病。生存取决于辅助通气、基础疾病的治疗以及肺部表面活性剂抑制的逆转。对必需的表面活性剂蛋白 B 和主要脂质进行重新设计以增强对抑制和氧化应激的抵抗力，可能会提供一种独特的能够治疗 ALI/ARDS 的合成表面活性剂制剂。