Examining Carbon Monoxide to Treat Inflammatory Conditions using Experimental Colitis Models

使用实验性结肠炎模型检查一氧化碳治疗炎症的作用

• 批准号: 10654693
• 负责人: LEO E OTTERBEIN
• 金额: $ 70.89万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654693
• 关键词: Acceleration; Acute; Animal Model; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; Bacterial Infections; Carbon Monoxide; Characteristics; Clinical; Clinical Trials; Clostridium difficile; Colitis; Colon; Cytoprotection; Data; Dedications; Defect; Dependence; Development; Disease; Dose; Drug Costs; Drug Kinetics; Foundations; Functional disorder; Funding; Future; Gases; Goals; Heme; Hospitals; Host Defense; Human; Immune Tolerance; Immune response; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inhalation; Innate Immune Response; Intestines; Ischemia; Kinetics; Lead; Light; Link; Literature; Macrophage; Mammals; Medical Genetics; Metals; Modality; Modeling; Mucous Membrane; Mus; Myocardial Infarction; Neoplasms; Nitric Oxide; Nobel Prize; Oral; Organ Transplantation; Oxygenases; Pathogenesis; Pathogenicity; Pharmaceutical Chemistry; Pharmacologic Substance; Pharmacology; Pharmacology and Toxicology; Physiology; Predisposition; Prodrugs; Property; Publications; Reperfusion Injury; Reporting; Research; Resolution; Respiratory physiology; Sepsis; Series; Signaling Molecule; Stroke; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Toxicology; United States National Institutes of Health; Work; clinical translation; design; dosage; drug development; drug discovery; dysbiosis; effective therapy; gut inflammation; gut microbiota; immune modulating agents; immunoregulation; improved; in vivo; indexing; individual patient; infection risk; inflammatory modulation; innovation; interdisciplinary approach; liver injury; metal poisoning; mouse model; novel; pathogenic bacteria; pharmacologic; portability; pre-clinical; prevent; protective effect; repaired; tissue injury; tissue repair; tool

Abstract Carbon monoxide (CO) is an endogenous signaling molecule with importance on par with nitric oxide (NO), the subject of the 1998 Nobel Prize. It is produced from heme degradation by heme oxygenases. Extensive literature reports have convincingly demonstrated the therapeutic effects of CO as an anti-inflammatory agent in models of colitis, sepsis, liver injury, and organ transplant. While much is known regarding the efficacy of CO, the challenge now is to develop pharmaceutically acceptable deliverable forms of CO as research tools and possible therapeutics. Inhaled CO has been the major form of delivery in most preclinical work. However, this is not the ideal modality because of difficulties in safe administration and in controlling doses, lack of portability, and the dependence on each individual patient’s respiratory function to deliver precise amounts. There have also been a number of metal-based CO-releasing molecules (CO-RMs) and photo-sensitive organic CO-RMs. However, metal toxicity and light accessibility issues impose limitations. In an exciting development, we have developed several classes of organic CO-prodrugs with tunable release rates. We propose to explore the potential of using such prodrugs to treat inflammation and tissue injury using experimental colitis (EC) in mice as a model. Others and we have demonstrated the unique ability of CO to reduce inflammation, promote tissue repair, and enhance host defense against pathogenic bacterial infection. Therefore, CO has enormous potential to be an effective treatment for colitis without the increased risk of infection associated with broad immunosuppression. With the high cost of drug discovery and development which is way beyond the funds available in an NIH application, we plan to initially examine a well-defined set of issues. The availability of prodrugs with tunable release rates offers the opportunity for the first time to examine the interplay among dosage, efficacy, pharmacokinetics, and release profiles, which is a unique problem with a gasotranmistter. In this MPI application, we combine the extensive expertise of the Wang, Tan, and Otterbein labs, and propose to build on compelling preliminary data to develop organic CO-prodrugs for treating inflammation in EC models. Our central hypothesis is that CO-prodrugs acts therapeutically in EC by modulating the intestinal microenvironment. We will test this with the following 2 specific aims: 1.) synthesize, optimize, and assess CO prodrugs; and 2.) evaluate the CO-prodrugs in EC. Our preliminary results clearly show efficacy of such CO-prodrugs in treating murine EC, sepsis, and liver injury. Upon completion of the project, we expect to have: 1.) developed a series of CO prodrugs, 2.) demonstrated the feasibility of using such prodrugs to treat inflammation in EC models; and (3) defined the relationship among dose, release kinetics, pharmacokinetics and efficacy with a clear therapeutic window. The clinical potential of CO-based therapeutics as anti-inflammatory agents is profound and could impact other areas such as organ transplantation, stroke, and heart attack.

抽象的 一氧化碳（CO）是一种内源性信号分子，重要性与一氧化氮（NO）， 1998年诺贝尔奖的主题。它是由血红素氧酶降解产生的。广泛的 文献报告令人信服地证明了CO作为抗炎药的治疗作用 在结肠炎，败血症，肝损伤和器官移植的模型中。虽然对效率有很多了解 CO，现在的挑战是开发出可接受的CO的物理可接受的交付形式作为研究工具 和可能的治疗学。吸入CO是大多数临床前工作的主要交付方式。然而， 这不是理想的方式，因为在安全管理和控制剂量方面难以 可移植性以及对每个患者呼吸功能的依赖性，以提供精确的量。 也有许多基于金属的共释放分子（Co-RMS）和光敏的分子 有机共同RMS。但是，金属毒性和轻便的可及性问题施加局限性。令人兴奋 开发，我们开发了几类具有可调释放速率的有机共同生产。我们 提议探索使用此类前药治疗感染和组织损伤的潜力 小鼠作为模型的实验性结肠炎（EC）。其他人，我们已经证明了CO的独特能力 减少感染，促进组织修复并增强宿主防御致病性细菌感染。 因此，CO具有对结肠炎的有效治疗的巨大潜力，而没有增加的风险 与广泛免疫抑制相关的感染。毒品发现和开发成本很高 这超出了NIH申请中可用的资金，我们计划最初检查一组明确定义的 问题。具有可调发行率的前药的可用性为首次进行考试提供了机会 剂量，有效性，药代动力学和释放轮廓之间的相互作用，这是一个独特的问题 Gasotranmister。在此MPI应用程序中，我们结合了Wang，Tan和Otterbein的广泛专业知识 实验室，以及建立引人注目的初步数据的建议，以开发有机共同生产以治疗 EC模型中的炎症。我们的中心假设是，共同生产在EC中热起作用 调节肠道微环境。我们将使用以下2个特定目标进行测试：1。）合成， 优化并评估CO前药；和2.）评估EC中的共同生产。我们的初步结果 显示此类共同产生在治疗鼠EC，败血症和肝损伤方面的效率。完成后 项目，我们期望：1。）开发了一系列CO前药，2。）证明了使用的可行性 这种前药治疗EC模型中的炎症； （3）定义剂量之间的关系，释放 动力学，药代动力学和效率清晰的治疗窗口。基于CO的临床潜力 作为抗炎剂的治疗是深远的，可能会影响其他领域，例如器官 移植，中风和心脏病发作。

项目成果

Carbon monoxide and a change of heart.

• DOI: 10.1016/j.redox.2021.102183
• 发表时间: 2021-12
• 期刊: Redox biology
• 影响因子: 11.4
• 作者: Chu LM;Shaefi S;Byrne JD;Alves de Souza RW;Otterbein LE
• 通讯作者: Otterbein LE

Toward "CO in a Pill": Silica-Immobilized Organic CO Prodrugs for Studying the Feasibility of Systemic Delivery of CO via In Situ Gastrointestinal CO Release.

• DOI: 10.1021/acs.molpharmaceut.2c01104
• 发表时间: 2023-03-06
• 期刊: MOLECULAR PHARMACEUTICS
• 影响因子: 4.9
• 作者: Yang, Xiaoxiao;Tripathi, Ravi;Wang, Minjia;Lu, Wen;Anifowose, Abiodun;Tan, Chalet;Wang, Binghe
• 通讯作者: Wang, Binghe

Towards "CO in a pill": Pharmacokinetic studies of carbon monoxide prodrugs in mice.

• DOI: 10.1016/j.jconrel.2020.07.040
• 发表时间: 2020-11-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Wang M;Yang X;Pan Z;Wang Y;De La Cruz LK;Wang B;Tan C
• 通讯作者: Tan C

Light-Activated CO Donor as a Universal CO Surrogate for Pd-Catalyzed and Light-Mediated Carbonylation.

• DOI: 10.1021/acs.orglett.2c01726
• 发表时间: 2022-07-15
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: de la Cruz, Ladie Kimberly;Bauer, Nicola;Cachuela, Alyssa;Tam, Wing Sze;Tripathi, Ravi;Yang, Xiaoxiao;Wang, Binghe
• 通讯作者: Wang, Binghe

"CO in a pill": Towards oral delivery of carbon monoxide for therapeutic applications.

• DOI: 10.1016/j.jconrel.2021.08.059
• 发表时间: 2021-10-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Yang X;Lu W;Wang M;Tan C;Wang B
• 通讯作者: Wang B