Chemical platform to produce covalent biologics

生产共价生物制剂的化学平台

基本信息

批准号：
10688088
负责人：
Alexander V Statsyuk
金额：
$ 18.34万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
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/10688088
关键词：
Address Amino Acyl-tRNA Synthetases Anti-Inflammatory Agents Antibodies Biological Biological Assay Biological Models Biological Products Biological Response Modifier Therapy 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 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 Transfer RNA Translating Underrepresented Minority Universities Work anakinra analog clinical candidate covalent bond crosslink drug discovery high risk high throughput screening human disease improved in vivo new technology novel therapeutics pharmacologic prevent programmed cell death protein 1 programs protein aggregation protein crosslink public health relevance receptor screening small molecule technology platform therapeutic cytokines therapeutic protein unnatural amino acids virtual

项目摘要

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.

项目概要拟议研究计划的目标是开发化学平台技术来生产和优化共价生物制剂——一种新的治疗方式。生物药是药品的一大组成部分然而，它们的缺点是价格高且需要频繁注射。我们假设共价生物制剂将具有更高的效力并且需要更少的注射频率。常规的生产共价生物制剂的方法依赖于非自然氨基酸诱变，但这种方法不是吞吐量并遭受蛋白质产量降低的影响。拟议的化学技术旨在通过提高共价生物产量克服这些挑战，允许快速合成和测试数百个一天内共价生物药物，并允许几乎无限数量的共价弹头安装在蛋白质表面。这是一个高风险提案，没有按照中的说明提供任何初步数据 PAR-19-254。我们最初的探索性研究将侧重于开发化学平台并对其进行验证在基于细胞的研究和在中使用免疫检查点抑制剂和抗炎蛋白疗法体内。这是一项联合 PI 提案，涉及休斯顿大学的 Alexander Statsyuk（在化学和蛋白质生物化学）和 Prairie View A&M 大学的 Victoria Mgbemena（专业知识为免疫学和小鼠生物学）。 Prairie View A&M 大学历史上属于黑人大学，大学，并为科学领域代表性不足的少数群体的学生群体提供服务。