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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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要天然产物（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。在过去的30年里，NP衍生药物占更多超过35%的FDA批准。尽管其重要性已得到证明，由于缺乏有效的发现，生产，和优化，再加上使用传统的生物测定指导的NP重新发现率高，隔离技术。最近，下一代测序和基因组挖掘算法这表明，自然界中存在着大量未经表征的天然产物，揭示了一个巨大的化学多样性和生物活性的未开发资源。释放NP的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综合的高- 用于快速（1）鉴定、（2）合成和（3）筛选的高通量（HT）技术平台新的NP在第二阶段，该技术平台将通过机器人技术实现自动化，前所未有的速度和吞吐量，实现NP发现和优化。该集成平台的实用性将首先在I期使用套索肽进行证明作为NP类的代表。套索肽是核糖体合成的，修饰肽（RIPPs），其显示独特的折叠拓扑结构，赋予化合物具有非凡的稳定性和无数有前途的生物活性。这项建议的目的是为了开发一种平台，该平台将显著扩展已知的套索肽，类似物，和目标。基因组和宏基因组数据挖掘将提供序列信息 HT产生套索肽所需的，所述套索肽将筛选生物活性（最初抗菌剂）。下文概述的拟议具体目标将通过 Genomatica，Inc.伊利诺斯大学的道格拉斯米切尔博士厄巴纳-香槟