High throughput chemoenzymatic synthesis of antimalarial compounds

抗疟化合物的高通量化学酶法合成

• 批准号: 10526962
• 负责人: Alison Narayan
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526962
• 关键词: Alkaloids; Amodiaquine; Anthraquinones; Antimalarials; Artemisinins; Biological Assay; Cessation of life; Chloroquine; Chloroquine resistance; Cinchona; Combined Modality Therapy; Complex; Complex Mixtures; Coupling; Cytochrome P450; Development; Disease; Drug resistance; Elements; Engineering; Ensure; Enzymes; Evaluation; Falciparum Malaria; Generations; Health; Human; Human Cell Line; Insecticides; Left; Libraries; Malaria; Malaria Vaccines; Medicine; Mefloquine; Natural Products; Parasites; Parasitic Diseases; Pathway interactions; Pharmaceutical Preparations; Plant Extracts; Plants; Plasmodium falciparum; Preventive; Preventive measure; Protein Engineering; Quinine; Reaction; Recording of previous events; Resistance; Site; Structure; Therapeutic; Therapeutic Agents; Trees; analog; asexual; base; catalyst; design; drug distribution; effective therapy; next generation; novel; prevent; programs; small molecule; social; success; transmission process; vaccine strategy

PROJECT SUMMARY Malaria continues to pose a significant threat to human health with over 200 million cases each year and nearly 500,000 deaths worldwide. These staggering numbers illustrate the magnitude of this parasitic disease despite preventive programs such as insecticide-treated nets and available drugs. Thus, combatting this disease will require a multiprong approach that includes preventative measures such as vaccines and strategies to minimize transmission as well as effective treatments. Although recent advances in a malaria vaccine and social programs are poised for success, the efficacy of available small molecule drugs is threatened by the exponential rise in drug-resistance in Plasmodium falciparum (P. falciparum). For example, chloroquine resistance has steadily spread with the broad distribution of this drug first introduced in 1945 and resistance has already emerged toward artemisinin-based combination therapy (ACT) first administered in the mid-2000's. Based on this trajectory, there is a dire need for the development of novel small molecule antimalarial drugs. Historically, natural plant metabolites have provided the basis for potent antimalarial drugs. For example, quinine, the first antimalarial drug which is isolated from the bark of the Cinchona tree, provided the structural basis for the most widely used small molecule malaria treatment in history, chloroquine. Similarly, artemisinin is also a plant natural product, which has become the favored treatment for falciparum malaria and is often administered along with different classes of antimalarial drugs including mefloquine and amodiaquine. The complex structures of natural products, like artemisinin, can complicate or even completely derail the development of natural metabolites with promising antimalarial activity as therapeutic agents. This has left potent antiplasmodial natural products underexplored. For example, plant natural products, such as naphthylisoquinoline alkaloids and aryl anthraquninones, display potency against P. falciparum and selectivity for the parasite over human cell lines that exceeds chloroquine, yet restricted access to the natural compounds and synthetic analogs has limited the development of these compounds as medicines. To overcome the challenges associated with constructing complex biaryl natural products such as naphthylisoquinoline alkaloids and aryl anthraquinones through traditional synthesis, we propose a convergent chemoenzymatic approach toward this class of molecules. The biosynthetic pathways related to naphthylisoquinone and aryl anthraquinone plant metabolites have not been identified, therefore, we envision adapting enzymes associated with bacterial and fungal biosynthetic pathways for this purpose. We will employ a high throughput protein engineering strategy to tune and ensure access to enzymes with suitable substrate scope and desired site- and atroposelectivity. With the ability to rapidly generate targeted natural product classes and analogs thereof, we will be poised to interrogate the structural elements that contribute to their efficacy and optimized these compounds as next-generation antimalarial drugs.

项目摘要 疟疾继续对人类健康构成重大威胁，每年有2亿多病例， 全球50万人死亡。这些惊人的数字说明了这种寄生虫病的严重性， 预防计划，如驱虫蚊帐和可用的药物。因此，防治这种疾病将 需要多管齐下的方法，包括预防措施，如疫苗和战略， 传播以及有效的治疗。尽管疟疾疫苗和社会项目的最新进展 已经做好了成功的准备，可用的小分子药物的功效受到了指数增长的威胁， 恶性疟原虫（Plasmodium falciparum）的抗药性。例如，对氯喹的抗药性 随着1945年首次引入的这种药物的广泛分布而传播， 青蒿素为基础的联合疗法（ACT）在2000年中期首次使用。根据这个轨迹， 迫切需要开发新型小分子抗疟药物。 从历史上看，天然植物代谢物为有效的抗疟疾药物提供了基础。比如说， 奎宁是第一种从金鸡纳树皮中分离出来的抗疟疾药物， 历史上最广泛使用的小分子疟疾治疗药物氯喹的基础。同样，青蒿素是 也是一种植物天然产物，已成为恶性疟疾的首选治疗方法， 沿着不同种类的抗疟药，包括甲氟喹和阿莫地喹。的 天然产物的复杂结构，如青蒿素，可以使其复杂化，甚至完全脱轨。 开发具有抗疟活性的天然代谢物作为治疗剂。这使得强大的 抗疟原虫的天然产物还未充分开发。例如，植物天然产品，如 萘异喹啉生物碱和芳基蒽醌类，显示出抗恶性疟原虫的效力和选择性 对人体细胞系的寄生虫，超过氯喹，但限制获得天然化合物， 和合成类似物限制了这些化合物作为药物的开发。 为了克服与构建复杂的联芳基天然产物， 萘异喹啉类生物碱和芳基蒽醌类化合物的传统合成方法， 化学酶的方法对这类分子。生物合成途径与 萘异醌和芳基蒽醌植物代谢物尚未确定，因此，我们设想， 使与细菌和真菌生物合成途径相关的酶适应于此目的。我们会委聘 高通量蛋白质工程策略，以调整并确保获得具有合适底物的酶 范围和所需部位-以及atroposelectivity。能够快速生成目标天然产品类别 及其类似物，我们将准备询问有助于其功效的结构元件， 优化这些化合物作为下一代抗疟疾药物。