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Biocatalytic generation of bioactive biaryl natural products

生物催化生成生物活性联芳天然产物

基本信息

批准号：
10395476
负责人：
Lara Emily Zetzsche
金额：
$ 0.58万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2020-06-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395476
关键词：
AIDS/HIV problem Address Africa Alkaloids Anabolism Antimalarials Architecture Biochemical Biological Cardiovascular system Chemicals China Communicable Diseases Coupled Coupling Cytochrome P450 Development Directed Molecular Evolution Engineering Enzymes Exhibits Fever Garcinia kola Generations HIV Harvest Health Hepatitis B Hepatitis B Virus Human In Vitro Inflammation Libraries Malaria Malaysia Malignant Neoplasms Mass Spectrum Analysis Membrane Metabolic Diseases Methods Modernization Mutagenesis Natural Products Nature Neuraxis Oncology Organic Synthesis Oxidation-Reduction Parasitic infection Pharmacology Phenols Plant Roots Plants Property Proteins Reaction Recording of previous events Research Seeds Site Source Structure Therapeutic Traditional Medicine Variant Women&apos s Health Work Yeasts anti-hepatitis B anticancer activity bioactive natural products catalyst chemical synthesis drug discovery fungus men non-Native novel scaffold therapeutic development

项目摘要

PROPOSAL SUMMARY Plants that produce biaryl natural products have a long history of medicinal use in naturopathic remedies due to the potent biological activities manifested by the biaryl architecture of these molecules. Over the last several decades, the biaryl scaffold has been widely acknowledged as a privileged structure in drug discovery; however, the full exploration of the medicinal properties and therapeutic development of natural products harboring biaryl scaffolds is hindered by the inability to isolate significant quantities of these compounds through natural sources or chemical synthesis. The potent biological activities of these natural products are contingent upon the axial chirality of the biaryl bond, yet forming a biaryl bond with this selectivity and precision remains a fundamental challenge in organic synthesis which has limited our access to these natural products. In contrast, Nature has evolved enzymes capable of forming these critical biaryl bonds with excellent selectivity. I aim to engineer these enzymes into robust biocatalysts capable of catalyzing the formation of axially chiral biaryl bonds with catalyst- controlled site-selectivity unmatched with conventional chemical methods. Through the directed evolution of these enzymes, I will synthesize biaryl natural products that have demonstrated potent and diverse biological activity, yet are currently understudied primarily due to their current inaccessibility. The two classes of biaryl natural products that I aim to access are biflavonoids and naphthylisoquinoline alkaloids. Both of these classes of natural products harbor the privileged axially chiral biaryl architecture and have demonstrated largely untapped therapeutic potentials. Most significantly, many biflavonoids exhibit anti-hepatitis B virus and anticancer activity and many naphthylisoquinoline alkaloids exhibit antimalarial and anti-HIV activity. Developing this biocatalytic platform will provide access to a library of these pharmacologically promising natural products and their derivatives, thereby accelerating their therapeutic development for applications including hepatitis B, cancer, malaria, and HIV/AIDS.

提案摘要产生联芳基天然产物的植物在自然疗法中具有很长的药用历史，这是由于这些分子的联芳基结构所表现出的有效的生物活性。过去几几十年来，联芳基支架被广泛认为是药物发现中的优先结构;然而，对含联芳基的天然产物的药用特性和治疗开发进行了充分的探讨由于不能通过天然来源分离大量的这些化合物，或化学合成。这些天然产物的有效的生物活性取决于轴向尽管如此，形成具有这种选择性和精确度的联芳基键仍然是基本的有机合成的挑战限制了我们获得这些天然产物。相比之下，大自然进化的酶能够以优异的选择性形成这些关键的联芳基键。我的目标是设计这些将酶转化为能够催化轴向手性联芳基键形成的稳健的生物催化剂，与传统化学方法无法比拟的受控的位点选择性。通过定向进化，这些酶，我将合成联芳基天然产物，已被证明有效和多样化的生物活性，活动，但目前研究不足，主要是由于他们目前无法进入。两类联芳基天然产物，我的目标是访问双黄酮和萘异喹啉生物碱。这两个类的天然产物具有特殊的轴向手性联芳基结构，治疗潜力最重要的是，许多双黄酮类化合物表现出抗B型肝炎病毒和抗癌活性并且许多萘异喹啉生物碱表现出抗疟疾和抗HIV活性。开发这种生物催化剂平台将提供访问这些有前途的天然产品及其衍生物，从而加速了它们在包括B型肝炎，癌症，疟疾和艾滋病毒/艾滋病