Production Scale-Up and Target Identification of the Antioxidant Ergothioneine

抗氧化剂麦角硫因的生产放大和靶点鉴定

• 批准号: 10056054
• 负责人: Pinghua Liu
• 金额: $ 0.77万
• 依托单位: ERGO HEALTH, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056054
• 关键词: Address; Aging; Anabolism; Animal Model; Animals; Antioxidants; Biological; Biology; Boston; Caenorhabditis elegans; Cardiovascular Diseases; Chemicals; Chronic Disease; Collaborations; Cosmetics; Crohn' s disease; Diabetes Mellitus; Diet; Disease; European; Evaluation; Fermentation; Food Safety; Food Supplements; Fortified Food; Genetic; Glutathione; Grant; Growth; Health; Healthcare; Healthcare Systems; Human; Human body; Institutes; Intervention; Isomerism; Kilogram; Legal patent; Length; Life; Life Expectancy; Life Extension; Link; Longevity; Medical; Medicine; Methods; Modeling; National Institute on Aging; Neurodegenerative Disorders; Nutraceutical; Organ; Outcome; Pathway interactions; Patients; Penetration; Pharmacologic Substance; Phase; Play; Population; Price; Private Sector; Process; Production; Quality of life; Reactive Nitrogen Species; Reactive Oxygen Species; Research; Research Personnel; Rheumatoid Arthritis; Role; Sampling; Savings; Scientist; Signal Pathway; Stereoisomer; Sulfhydryl Compounds; System; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; United States National Institutes of Health; Universities; Work; World Health Organization; age related; anti aging; authority; base; cGMP production; chemical synthesis; comparative; cost; drug development; drug discovery; healthspan; human disease; improved; in vivo; large scale production; mouse model; phase 1 study; product development; programs; racemization; scale up; tool

ABSTRACT Ergothioneine is one of the most abundant thiols in many parts of the human body and several diseases have been linked to ergothioneine insufficiency, including rheumatoid arthritis, Crohn's disease, neurodegenerative diseases, cardiovascular disorders and diabetes. Animals do not synthesize ergothioneine and, instead, obtain it from their diet through an ergothioneine-specific transporter (OCTN1) with accumulation up to mM concentrations in several organs and tissues. Due to their differences in reduction potential (E0' = - 0.06 V for ergothioneine and E0' = - 0.24 V for glutathione), a combination of ergothioneine and glutathione provide cellular protection over a wide range of conditions such as against reactive oxygen species (ROS) and reactive nitrogen species (RNS). Despite ergothioneine's demonstrated role in maintaining human health, the current method used to produce it has proved to be a bottleneck in its widespread use. Specifically, the chemical synthesis method suffers from racemization of a stereo-center with the byproduct isomer being toxic. As a result, production at a large scale is both challenging and costly. In our preliminary studies, we developed an alternative, fermentation-based biosynthetic production method capable of producing 10 grams/liter on a 1 L batch-scale. In addition, we have identified the signaling pathway(s) related to ergothioneine function. These breakthroughs in supply and mechanistic understanding provide the scientific and manufacturing support necessary to realize ergothioneine's full commercial potential, which includes: further growth of its share in the cosmetic market, expansion into new markets (e.g., as a component in nutraceuticals), or for drug discovery and development. In this proposal we will address two key go/no-go questions that will guide the further development of this product. Specifically, we will scale-up the synthesis to pilot scale production using our patented ergothioneine production technology and also pinpoint ergothioneine's biological targets. To this end, the aims are: Aim 1: Achieve pilot-scale (100's g – 1 kg) production of ergothioneine with purity >99%. Aim 2: Verify the ergothioneine-related signaling pathways. Outcomes. Upon successful completion of these studies, we will apply for a Phase II grant with aims of large- scale production under good manufacturing practices to support additional market penetration and expansion. At the same time, we will re-examine ergothioneine's impact on ageing and age-related disease in vivo. We will also reach out to other scientists in the anti-ageing field to seek collaboration, including collaboration with an existing NIH anti-ageing program (https://www.nia.nih.gov/research/dab/interventions-testing-program-itp).

抽象的 Ergothiine是人体许多部位中最丰富的硫醇之一，几种疾病具有 与果仁氨酸不足有关，包括类风湿关节炎，克罗恩病，神经退行性 疾病，心血管疾病和糖尿病。动物不合成甲氨酸，而是获得 它从饮食到Ergotheine特异性转运蛋白（OCTN1），积累高达mm 几个器官和组织中的浓度。由于它们的降低电势差异（E0'= -0.06 V Ergothionine和E0'= -0.24 V，用于谷胱甘肽），Ergothione和Glutathione的组合提供 在多种条件下的细胞保护，例如反应性氧（ROS）和活性 氮种（RNS）。尽管Ergothionine在维持人类健康中表现出了作用，但目前 用于生产它的方法已被证明是其宽度使用的瓶颈。具体而言，化学物质 合成方法遭受立体中心的种族化，副产品异构体有毒。作为 结果，大规模的生产既是挑战又是昂贵的。在我们的初步研究中，我们开发了 基于发酵的替代性生物合成生产方法，能够在1 L上产生10克/升 批量级。此外，我们已经确定了与ergotheine功能有关的信号通路。这些 供应和机械理解的突破提供了科学和制造支持 实现Ergotheine的全部商业潜力所必需的，其中包括：进一步增长其在 化妆品市场，扩展到新市场（例如，作为营养学的组成部分）或用于药物发现 和发展。在此提案中，我们将解决两个关键的问题/不进行问题，这些问题将进一步指导 该产品的开发。特别是，我们将使用我们的 获得专利的Ergothionine生产技术，并确定Ergotheine的生物靶标。为此， 目的是： AIM 1：实现纯度> 99％的Ergothineine生产的试验尺度（100's G - 1 kg）。 AIM 2：验证与Ergotheine相关的信号通路。 结果。这些研究成功完成后，我们将申请II阶段赠款，其目标很大 在良好的制造实践下进行规模生产，以支持额外的市场渗透和扩张。 同时，我们将重新检查ergothionine对体内衰老和与年龄相关的疾病的影响。我们将 还与抗衰老领域的其他科学家联系以寻求合作，包括与 现有的NIH抗年龄计划（https://www.nia.nih.gov/research/dab/interventions-testing-program-itp）。