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.

项目摘要天然产品（NP）及其衍生物为药物提供了丰富的化学物质来源发现与发展。在过去的30年中，NP衍生的药物占了更多超过35％的FDA批准。尽管它们很重要，但发展了新的NP 由于缺乏有效的发现，生产方法，过去15年来一直放缓和优化，再加上NP的高速率，使用传统生物测定引导隔离技术。最近，下一代测序和基因组开采算法表明自然界中存在大量未表征的天然产品，揭示了广阔的化学多样性和生物活性的未开发的来源。解锁NP的潜在潜力根据基因组开采的预测，我们提出的第一阶段研究旨在发展综合的高位快速（1）识别，（2）合成的吞吐量（HT）技术平台，以及（3）筛选新的NP。在第二阶段，该技术平台将与机器人技术自动化以提供 NP发现和优化的前所未有的速度和吞吐量。该集成平台的实用性首先将在第一阶段使用套索肽进行演示作为代表性的NP类。拉索肽是核糖体合成的，并在翻译后进行后改性肽（RIPP）显示出独特的折叠拓扑，该拓扑赋予化合物非凡的稳定性和无数有希望的生物学活动。该提议的目的是开发一个平台，该平台将大大扩展已知的套索肽，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生成的套索肽所必需的，该肽将被筛选以进行生物活性（最初抗菌）。下面概述的拟议的具体目的将通过 Genatoma，Inc。和伊利诺伊大学的Douglas Mitchell博士之间的合作 Urbana-Champaign。