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Development of a Biocatalytic Toolbox for the Synthesis of Small-Molecule Mimics of cyclic GMPAMP

开发用于合成环状 GMPAMP 小分子模拟物的生物催化工具箱

基本信息

批准号：
10751277
负责人：
Cole Christian Meyer
金额：
$ 6.87万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751277
关键词：
Address American Antineoplastic Agents Chemicals Clinical Clinical Trials Communities Complex Constitution Constitutional Cyclic GMP Data Development Dinucleoside Phosphates Drug Compounding Drug Targeting Eating Engineering Enzymes Fellowship Friends Generations Health Homologous Gene Human Hydroxyl Radical Immunotherapeutic agent Investigation Isomerism Knowledge Libraries Malignant Neoplasms Methodology Methods Modification Nature Nucleosides Periodicity Pharmaceutical Preparations Pharmacologic Substance Phase Phosphorus Preparation Process Protein Engineering Proteins Reference Standards Reporting Research Route STING agonists Scientist Site Structure Technology Therapeutic Variant Vertebral column Work analog cancer immunotherapeutics cancer therapy catalyst clinical candidate cost drug efficacy high throughput screening improved inorganic phosphate insight manufacture non-Native novel novel therapeutics nucleobase phosphorothioate screening small molecule statistics

项目摘要

PROJECT SUMMARY/ABSTRACT Twenty percent of Americans die of cancer. This alarming statistic reflects a major human health need for novel cancer therapeutics. Small molecule mimics of cyclic GMP-AMP (cGAMP) represent an emerging new class of immunotherapeutic cancer drugs, and numerous cGAMP-mimics have been entered into clinical trials in the last three years. Unfortunately, due to their unusually complex structure, these clinical candidates are exceptionally difficult to prepare via classic synthetic methodology, which serves as a limitation to their development. Recent advances in biocatalysis, however, indicate significant opportunity to simplify the synthesis of cGAMP-mimics. The enzyme that naturally produces cGAMP is called cGAMP synthase (cGAS), and preliminary results suggest that engineering of cGAS may provide a way to access diverse cGAMP-mimics through a highly direct process. This proposal aims to develop biocatalytic approaches for the synthesis of cGAMP-mimics using natural and engineered cGAS variants. As over 500 sequences of cGAS enzymes have been catalogued from nature, there is already a large protein library from which to develop an expanded biocatalytic lexicon for the synthesis of cGAMP-mimics. There are three major challenges in the synthesis of unnatural cGAMP-mimics that will be ad- dressed by this fellowship, which aims to 1) build a panel of cGAS enzymes with non-native nucleobase toler- ance, 2) create stereocomplementary catalysts for phosphorothioate centers, and 3) engineer cGAS to create atypical constitutional isomers of cGAMP. It is our hypothesis that novel reactivity and selectivity can be realized through a two-phase iterative interrogation of cGAS proteins: high-throughput screening of a library of cGAS enzymes against a reference target followed by engineering of the most successful variants. Insights from this work will afford an increased knowledge of the specific structural features of cGAS that govern nucleobase tol- erance, phosphorus-centered stereoselectivity, and site-selectivity in macrocyclization. This work will enable sci- entists to develop tomorrow’s immunotherapeutic cancer drugs more rapidly.

项目总结/文摘