SBIR Phase I: A Natural Product Drug Discovery Platform Based on High-Throughput Elicitor Screening (HiTES)

SBIR 第一期：基于高通量诱导子筛选（HiTES）的天然产物药物发现平台

• 批准号: 2150951
• 负责人: Jennifer Levine
• 金额: $ 25.6万
• 依托单位: CRYPTYX BIOSCIENCE, INC.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2150951&HistoricalAwards=false
• 关键词: SBIR; Phase; Natural; Product; Drug

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project will be the development of a novel, small-molecule drug discovery platform that triggers the production of cryptic microbial metabolites for use as new pharmaceuticals with the potential to target a range of diseases. This technology will address pain points associated with the development of new drugs, such as long timelines and high costs. By using a proprietary process and established collection of elicitor molecules, microorganisms can be compelled to generate natural products that offer biological activities that may be impossible with synthetic molecules. The proposed technology is the only screening platform that is free of genetics and cloning, focusing on bioactivity first, and enabling rapid and efficient biomolecule discovery. Initially the platform will be used to target the antibiotic/antiviral market, with future applications for anti-tumor and immunosuppressant drugs. This project has the potential to improve the health of the American public by providing a steady stream of novel drug candidates to address a range of unmet medical needs. This Small Business Innovation Research (SBIR) Phase I project aims to develop a novel, small-molecule drug discovery platform based on High-Throughput Elicitor Screening (HiTES), a rapid, simple method for triggering production of microbial cryptic metabolites and interrogating their activities without the need for genome sequencing, cloning, or genetics. There is a large untapped store of natural products in the form of ‘cryptic’ biosynthetic gene clusters encoded in microbial genomes that are not expressed under laboratory conditions. The technical objectives are to increase output/throughput of the platform, assess and optimize chemical diversity, and expand the platform to new antibiotic-resistant pathogens of public health concern. Silent genes across multiple bacterial species will be activated to generate cryptic metabolites with the goal of producing 5,000 induced metabolomes, which will be characterized using mass spectrometry. A workflow will be created that integrates bioactivity assays against multiple pathogens with HiTES screening. Finally, in-house software will be updated to include prioritization in terms of novel chemistry, desired bioactivity, and lack of cytotoxicity. Successful Phase I completion will demonstrate the ability to implement and use HiTES multiplexed with bioactivity studies and software to identify chemically-novel and unique compounds with promising bioactivities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项小型企业创新研究（SBIR）I阶段项目的更广泛的影响/商业潜力将是开发一种新型的小分子药物发现平台，该平台触发了使用隐型药物代谢物的生产，以用作新药物，并有可能靶向一系列疾病。这项技术将解决与新药的开发相关的疼痛点，例如长时间的时间表和高成本。通过使用专有过程并确定了诱发物分子的收集，可以强迫微生物生成天然产物，这些天然产物提供生物学活性，而合成分子可能是不可能的。提出的技术是唯一没有遗传学和克隆的筛选平台，首先关注生物活性，并实现快速有效的生物分子发现。最初，该平台将用于针对抗生素/抗病毒市场，并在未来的抗肿瘤和免疫抑制药物中应用。该项目有可能通过提供稳定的新型候选药物来满足一系列未满足的医疗需求，从而改善美国公众的健康状况。这项小型企业创新研究（SBIR）I阶段项目旨在基于高通量引发筛选（HITES）开发一种新型的，小分子的药物发现平台，这是一种快速，简单的方法，用于触发微生物加密代谢物的产生，并询问其活动而无需进行基因组测序，克隆或遗传学。在实验室条件下未表达的微生物基因组中编码的“隐秘”生物合成基因簇的形式有大量的未开发的天然产物。技术目标是增加平台的产出/吞吐量，评估和优化化学多样性，并将平台扩展到新的公共卫生抗生素病原体。多种细菌种类的无声基因将被激活以产生加密代谢产物，目的是产生5,000个诱导的代谢组，这些代谢组将使用质谱法进行表征。将创建一个工作流程，该工作流与HITES筛查相结合的多种病原体。最后，内部软件将进行更新，以包括新的化学，所需的生物活性和缺乏细胞毒性的优先级。成功的第一阶段完成将证明能够实施和使用杀手与生物活性研究和软件多样地识别具有承诺生物活性的化学新颖和独特化合物。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子优点和更广泛影响的审查标准来通过评估而被认为是珍贵的支持。