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 麦角硫因是人体许多部位最丰富的硫醇之一，与多种疾病有关 与麦角硫因不足有关，包括类风湿性关节炎、克罗恩病、神经退行性疾病 疾病、心血管疾病和糖尿病。动物不合成麦角硫因，而是获得 它通过麦角硫因特异性转运蛋白 (OCTN1) 从饮食中吸收，累积量高达 mM 多个器官和组织中的浓度。由于它们的还原电位不同（E0' = - 0.06 V 麦角硫因和 E0' = - 0.24 V（谷胱甘肽）），麦角硫因和谷胱甘肽的组合提供 在多种条件下提供细胞保护，例如对抗活性氧 (ROS) 和活性氧 氮物种（RNS）。尽管麦角硫因在维持人类健康方面具有明显的作用，但目前 事实证明，其生产方法是其广泛使用的瓶颈。具体来说，化学 合成方法存在立体中心外消旋化的问题，且副产物异构体有毒。作为一个 结果，大规模生产既具有挑战性又成本高昂。在我们的初步研究中，我们开发了一种 另一种基于发酵的生物合成生产方法，能够在 1 L 中生产 10 克/升 批量规模。此外，我们还确定了与麦角硫因功能相关的信号通路。这些 供应和机理理解的突破提供了科学和制造支持 实现麦角硫因的全部商业潜力所必需的，其中包括： 进一步增加其在 化妆品市场、拓展新市场（例如，作为营养保健品的成分）或用于药物发现 和发展。在本提案中，我们将解决两个关键的“进行/不进行”问题，以指导进一步的工作。 该产品的开发。具体来说，我们将利用我们的技术将合成规模扩大到中试规模生产 获得专利的麦角硫因生产技术，并精确定位麦角硫因的生物靶点。为此， 目标是： 目标 1：实现麦角硫因的中试规模（100 克 – 1 千克）生产，纯度 >99%。 目标 2：验证麦角硫因相关信号通路。 结果。成功完成这些研究后，我们将申请第二阶段拨款，目的是： 根据良好制造规范进行规模生产，以支持进一步的市场渗透和扩张。 同时，我们将重新审视麦角硫因对体内衰老和年龄相关疾病的影响。我们将 还与抗衰老领域的其他科学家寻求合作，包括与 现有的 NIH 抗衰老计划 (https://www.nia.nih.gov/research/dab/interventions-testing-program-itp)。