A Genes-to-Molecules Platform for Expanding Natural Product Diversity

用于扩大天然产品多样性的基因到分子平台

• 批准号: 9918085
• 负责人: Mark J Burk
• 金额: $ 22.5万
• 依托单位: LASSOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918085
• 关键词: Algorithms; Anabolism; Binding Sites; Bioinformatics; Biological; Biological Assay; Cells; Chemicals; Cloning; Collaborations; Collection; Complement; Coupled; Custom; DNA; DNA biosynthesis; Data; Data Set; Databases; Deposition; Development; Enzymes; FDA approved; Family; Genbank; Gene Cluster; Generations; Genes; Genetic Transcription; Genome; Genomics; Goals; Hour; Illinois; In Vitro; Industrialization; Institutes; Investigation; Joints; Lasso; Libraries; Metagenomics; Methods; Mining; Molecular; Natural Products; Natural Resources; Nature; Pathway interactions; Peptide Biosynthesis; Peptides; Pharmaceutical Preparations; Phase; Production; Publishing; Reporting; Ribosomes; Robotics; Small Business Technology Transfer Research; Source; Speed; System; Techniques; Technology; Therapeutic; Time; Tracer; Translating; Translations; Universities; Work; antimicrobial; base; cost; data mining; drug development; drug discovery; high throughput technology; improved; in silico; innovation; interest; metagenome; next generation sequencing; novel; novel diagnostics; peptide analog; phase 1 study; programs; protein aminoacid sequence; screening

Project Summary Natural products (NPs) and derivatives thereof provide a rich source of chemical matter for drug discovery and development. Over the past 30 years, NP-derived drugs have accounted for more than 35% of FDA approvals. Despite their demonstrated importance, development of new NPs has slowed over the past 15 years due to the lack of efficient methods for discovery, production, and optimization, coupled with the high rate of NP rediscovery using traditional bioassay-guided isolation techniques. Recently, next generation sequencing and genome-mining algorithms suggest that a wealth of uncharacterized natural products exist in Nature, revealing a vast untapped source of chemical diversity and biological activity. To unlock the latent potential of NPs predicted from genome-mining, our proposed Phase I study aims to develop an integrated high- throughput (HT) technology platform for rapidly (1) identifying, (2) synthesizing, and (3) screening new NPs. In Phase II, this technology platform will be automated with robotics to provide unprecedented speed and throughput for NP discovery and optimization. The utility of this integrated platform first will be demonstrated during Phase I using lasso peptides as a representative NP class. Lasso peptides are ribosomally synthesized and post translationally modified peptides (RiPPs) that display a unique folded topology that endows the compounds with extraordinary stability and a myriad of promising biological activities. The aim of this proposal is to develop a platform that will significantly expand the known repertoire of lasso peptides, analogs, and targets. Genomic and metagenomic data mining will provide the sequence information required for HT generation of lasso peptides that will be screened for biological activity (initially antimicrobial). The proposed specific aims outlined below will be achieved through the collaboration between Genomatica, Inc. and Dr. Douglas Mitchell at the University of Illinois at Urbana-Champaign.

项目概要 天然产物（NPs）及其衍生物为药物提供了丰富的化学物质来源 发现和发展。过去30年，NP衍生药物占了越来越多的份额 超过 35% 的 FDA 批准。尽管它们已被证明很重要，但新纳米颗粒的开发 由于缺乏有效的发现、生产、 和优化，再加上使用传统生物测定引导的 NP 重新发现率很高 隔离技术。最近，下一代测序和基因组挖掘算法 表明自然界中存在大量未表征的天然产物，揭示了巨大的 化学多样性和生物活性的未开发来源。释放纳米粒子的潜在潜力 根据基因组挖掘预测，我们提出的第一阶段研究旨在开发一种集成的高 通量 (HT) 技术平台，用于快速 (1) 识别、(2) 合成和 (3) 筛选 新的NP。在第二阶段，该技术平台将通过机器人实现自动化，以提供 NP 发现和优化的速度和吞吐量前所未有。 该集成平台的实用性将首先在第一阶段使用套索肽得到证明 作为NP类的代表。 Lasso 肽是核糖体合成的，并且是翻译后合成的 修饰肽（RiPP）显示出独特的折叠拓扑结构，赋予化合物 非凡的稳定性和无数有前景的生物活性。该提案的目的是 开发一个平台，将显着扩展套索肽、类似物的已知库， 和目标。基因组和宏基因组数据挖掘将提供序列信息 HT 生成套索肽所需的，将筛选其生物活性（最初 抗菌）。下面概述的拟议具体目标将通过 Genomatica, Inc. 与伊利诺伊大学 Douglas Mitchell 博士之间的合作 厄巴纳-香槟。

项目成果

Cell-Free Biosynthesis to Evaluate Lasso Peptide Formation and Enzyme-Substrate Tolerance.

用于评估套索肽形成和酶底物耐受性的无细胞生物合成。

• 发表时间: 2021
• 影响因子: 15
• 作者: Si, Yuanyuan;Kretsch, Ashley M;Daigh, Laura M;Burk, Mark J;Mitchell, Douglas A
• 通讯作者: Mitchell, Douglas A