Chemical platform to produce covalent biologics

生产共价生物制剂的化学平台

• 批准号: 10511039
• 负责人: Alexander V Statsyuk
• 金额: $ 23.59万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511039
• 关键词: Address; Amino Acids; Amino Acyl Transfer RNA; Amino Acyl-tRNA Synthetases; Anti-Inflammatory Agents; Antibodies; Biological; Biological Assay; Biological Models; Biological Products; Biology; Cells; Chemicals; Chemistry; Cysteine; Data; Engineering; Future; Historically Black Colleges and Universities; Hormones; Immune checkpoint inhibitor; Immunoglobulin Fragments; Immunology; In Vitro; Injections; Instruction; Insulin; KRAS2 gene; Knowledge; Literature; Metabolic; Methods; Modality; Monoclonal Antibodies; Mus; Mutagenesis; Nature; Pharmaceutical Preparations; Pharmacology; Population; Positioning Attribute; Price; Production; Protein Biochemistry; Proteins; Ras Inhibitor; Reaction; Reporting; Research; Science; Structure-Activity Relationship; Students; Surface; System; Technology; Testing; Therapeutic; Therapeutic Uses; Translating; Underrepresented Minority; Universities; Work; anakinra; analog; base; clinical candidate; covalent bond; crosslink; drug discovery; high risk; high throughput screening; human disease; improved; in vivo; new technology; novel; novel therapeutics; prevent; programmed cell death protein 1; programs; protein aggregation; public health relevance; receptor; screening; small molecule; therapeutic cytokines; therapeutic protein; virtual

PROJECT SUMMARY The objective of the proposed research program is to develop a chemical platform technology to produce and optimize covalent biologics - a new therapeutic modality. Biologic drugs constitute the large sector of drug discovery, however their downside is a high price and the need for frequent injections. We hypothesize that covalent biologics will have much higher potency and will need less frequent injections. The conventional methods to produce covalent biologics rely on unnatural aminoacid mutagenesis but this method is not throughput and suffer from the reduced protein production yields. The proposed chemical technology aims to overcome these challenges by improving covalent biologic yield, allowing rapid synthesis and testing of 100s of covalent biologic drugs in one day, and allowing virtually unlimited number of covalent warheads that can be installed on the protien surface. This is a high risk proposal without any preliminary data as per instructions in PAR-19-254. Our initial exploratory studies will focus on developing the chemical platform and validating it using immune checkpoint inhibitors and anti-inflammatory protein therapeutics in both cell based studies and in vivo. This is a Co-PI proposal involving Alexander Statsyuk from the University of Houston (expertise in chemistry and protein biochemistry) and Victoria Mgbemena from the Prairie View A&M University (expertise in immunology and mouse biology). Prairie View A&M University belongs to historically black colleges and universities, and serves student population who are underrepresented minorities in science.

项目摘要 拟议研究计划的目标是开发一种化学平台技术， 优化共价生物制剂-一种新的治疗方式。生物药品构成了药品的大部分 然而，它们的缺点是价格高，需要频繁注射。我们假设 共价生物制剂将具有高得多的效力，并且将需要较低频率的注射。常规 产生共价生物制剂的方法依赖于非天然氨基酸诱变，但该方法不是 生产能力降低，并遭受蛋白质产量降低的问题。拟议的化学技术旨在 通过提高共价生物产量来克服这些挑战，允许快速合成和测试数百种 共价生物药物，并允许几乎无限数量的共价弹头，可以 安装在蛋白质表面。这是一个高风险的建议，没有任何初步数据，按照说明， PAR-19-254我们最初的探索性研究将集中在开发化学平台和验证它 在基于细胞的研究和免疫学研究中使用免疫检查点抑制剂和抗炎蛋白治疗剂， vivo.这是一项共同主要研究者提案，涉及休斯顿大学的亚历山大·斯塔西克（擅长 化学和蛋白质生物化学）和维多利亚Mgbemena从草原视图A&M大学（专业知识， 免疫学和小鼠生物学）。Prairie View A&M University属于历史上的黑人大学， 大学，并服务于学生人口谁是科学代表不足的少数民族。