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.

提案摘要产生联芳天然产物的植物在自然疗法中具有悠久的药用历史，因为这些分子的联芳基结构表现出强大的生物活性。在过去的几个几十年来，联芳基支架已被广泛认为是药物发现中的一种特殊结构；然而，联芳天然产物的药用特性及治疗开发的充分探索由于无法通过天然来源分离大量这些化合物，支架受到阻碍或化学合成。这些天然产物的有效生物活性取决于轴向联芳键的手性，但以这种选择性和精确性形成联芳键仍然是一个基础有机合成的挑战限制了我们获取这些天然产品。相比之下，大自然却进化出的酶能够以优异的选择性形成这些关键的联芳键。我的目标是设计这些将酶转化为强大的生物催化剂，能够催化形成轴向手性联芳键受控的位点选择性是传统化学方法无法比拟的。通过定向进化这些酶，我将合成联芳天然产物，这些天然产物已被证明有效且多样化的生物活性活动，但目前尚未得到充分研究，主要是由于目前无法访问。联芳基的两类我想要获取的天然产品是双黄酮类化合物和萘基异喹啉生物碱。这两个类的天然产物具有独特的轴向手性联芳基结构，并且已被证明在很大程度上尚未开发治疗潜力。最重要的是，许多双黄酮类化合物具有抗乙型肝炎病毒和抗癌活性许多萘基异喹啉生物碱具有抗疟疾和抗艾滋病毒活性。开发这种生物催化平台将提供对这些具有药理学前景的天然产物及其库的访问衍生物，从而加速其治疗应用的开发，包括乙型肝炎、癌症、疟疾和艾滋病毒/艾滋病。