STTR Phase II: Enzymatic Synthesis of Chiral Cyclopropanes for Pharmaceutical Drug Synthesis and Agricultural Crop Protection Applications

STTR 第二阶段：用于药物合成和农作物保护应用的手性环丙烷的酶法合成

• 批准号: 1738308
• 负责人: David Rozzell
• 金额: $ 50万
• 依托单位: Provivi Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1738308&HistoricalAwards=false
• 关键词: STTR; Phase; II; Enzymatic; Synthesis

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) project is to establish a broadly applicable, breakthrough biocatalytic technology to produce an important class of compounds called chiral cyclopropanes. Cyclopropanes are key intermediates that are used in the synthesis of drugs, crop protection agents, and high-value electronic chemicals. Products accessible using this technology have markets totaling more than $10 billion annually. If successful, the technology under development will create safer, cleaner, more sustainable routes to important chemical products that will lower cost by reducing the number of production steps, lowering the required capital investment, significantly decreasing waste. Replacing existing chemical routes with the more efficient and sustainable enzyme-catalyzed steps will also improve the purity of many advanced pharmaceutical intermediates used in the manufacture of drugs and crop protection chemicals.This STTR Phase I project proposes to build on the results from Phase 1 in which a highly efficient biocatalytic process for the manufacture of the drug ticagrelor was developed using a novel, engineered enzyme. We will create an expanded set of cyclopropanation biocatalysts with the capability to act on a wider range of starting materials, thereby broadening the scope and utility of this new enzymatic reaction. We will complete the development and commercialization of the process for production of the key intermediate for ticagrelor and initiate work to develop novel biocatalysts to produce ley intermediates for anti-viral drugs. We will also develop and commercialize a set of enzymes that can be used by drug discovery chemists to establish efficient routes for next-generation drugs.

该小企业创新研究 (SBIR) 项目的更广泛影响/商业潜力是建立一种广泛适用的突破性生物催化技术，以生产一类重要的化合物，称为手性环丙烷。 环丙烷是用于合成药物、作物保护剂和高价值电子化学品的关键中间体。使用该技术的产品每年的市场总额超过 100 亿美元。如果成功，正在开发的技术将为重要化学产品创造更安全、更清洁、更可持续的路线，通过减少生产步骤数量、降低所需资本投资、显着减少浪费来降低成本。用更有效和可持续的酶催化步骤取代现有的化学路线还将提高用于制造药物和作物保护化学品的许多先进医药中间体的纯度。该 STTR 第一阶段项目建议以使用一种新型工程酶开发了一种用于制造药物替格瑞洛的高效生物催化工艺。我们将创建一套扩展的环丙烷化生物催化剂，能够作用于更广泛的起始材料，从而扩大这种新酶促反应的范围和实用性。我们将完成替格瑞洛关键中间体生产工艺的开发和商业化，并启动新型生物催化剂的开发工作，用于生产抗病毒药物的中间体。我们还将开发和商业化一组酶，药物发现化学家可以使用它们来建立下一代药物的有效途径。

项目成果

Highly Stereoselective Biocatalytic Synthesis of Key Cyclopropane Intermediate to Ticagrelor

高立体选择性生物催化合成替格瑞洛关键环丙烷中间体

• DOI: 10.1021/acscatal.6b02550
• 发表时间: 2016-10
• 期刊: ACS Catalysis
• 影响因子: 12.9
• 作者: Hernandez, Kari E.;Renata, Hans;Lewis, Russell D.;Kan, S. B.;Zhang, Chen;Forte, Jared;Rozzell, David;McIntosh, John A.;Arnold, Frances H.
• 通讯作者: Arnold, Frances H.