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

项目摘要 天然产物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衍生的药物占了更多 超过FDA批准的35%。尽管它们表现出了重要性，但新核动力源的开发 在过去的15年里，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指导的NP重新发现的高比率 隔离技术。最近，下一代测序和基因组挖掘算法 暗示自然界中存在着丰富的未经表征的天然产物，揭示了 未开发的化学多样性和生物活性来源。释放NPs的潜在潜力 根据基因组挖掘的预测，我们提议的第一阶段研究旨在开发一种综合的高度... 吞吐量(HT)技术平台，用于快速(1)鉴定、(2)合成和(3)筛选 新的NPs。在第二阶段，这一技术平台将通过机器人实现自动化，以提供 为NP发现和优化提供了前所未有的速度和吞吐量。 这个集成平台的用途将首先在第一阶段使用套索多肽进行演示 作为一个具有代表性的NP类。套索多肽是核糖体合成和翻译后的 修饰多肽(RIPP)，显示出独特的折叠拓扑结构，使化合物具有 非凡的稳定性和无数有前途的生物活性。这项提议的目的是 为了开发一个平台，它将显著扩展套索多肽、类似物、 和目标。基因组和元基因组数据挖掘将提供序列信息 产生HT所需的套索多肽，将进行生物活性筛选(最初 抗菌剂)。以下概述的拟议具体目标将通过 Genomatica，Inc.与伊利诺伊大学道格拉斯·米切尔博士的合作 乌尔巴纳-香槟。

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.