Chemoenzymatic synthesis and pharmacological evaluation of designer plant meroterpenoids
设计植物类萜的化学酶合成及药理评价
基本信息
- 批准号:10679446
- 负责人:
- 金额:$ 6.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAnabolismAngiospermsBacteriaBerberineBiochemicalBiologicalBiological ProcessBrainCannabidiolCannabinoidsCannabis sativa plantCellsChemistryCommunitiesCyclizationDataDevelopmentDrug KineticsEngineeringEnzymesEscherichia coliEvaluationEvolutionFermentationFlowersG-Protein-Coupled ReceptorsGenerationsHumanInvestigationLearningLibrariesLipidsLiteratureMetabolicMinorModificationNatural ProductsNeurodegenerative DisordersObesityPathway interactionsPharmacologyPharmacology StudyPhysiologicalPlantsProcessProductionPropertyResearch ProposalsRouteScientistSignal PathwaySignal TransductionSourceStreptomycesStructureStructure-Activity RelationshipTechnologyTerpenesTestingTetrahydrocannabinolTherapeuticYeastsanalogblood-brain barrier crossingchemical synthesischronic pain managementenzyme pathwayexperimental studyfungusliverwortmanufacturing facilitymarinemarine natural productmutantnon-Nativenovelnovel therapeuticspharmacologicpharmacophorephytocannabinoidpolyketide synthasepolyketidespreferenceprenylprenylationquinone methidescaffoldscreeningstereochemistrytargeted treatmenttherapeutic development
项目摘要
Project Summary/Abstract
Land plants like flowering plants and liverworts produce an array of natural products with various
biological functions. Polyketide meroterpenoids, comprising structures partially derived from terpenoid
biosynthetic pathways and partially derived from polyketide synthase biosynthetic pathways, have attracted
scientists for decades from their unique and diverse biological activity. Neuroactive plant meroterpenoids, like
phytocannabinoids from Cannabis sativa, represent a particularly exciting suite of compounds with therapeutic
promise due to their ability to cross the blood-brain barrier and engage GPCR targets. However, much of the
pharmacological data present in the literature to-date has focused on the cannabinoids, Δ9-tetrahydrocannabinol
(Δ9-THC) and cannabidiol (CBD), while minor constituents and unique analogs from other producers remain less
well studied. Lack of pharmacological data for these compounds is partly due to low accumulation of more rare
plant meroterpenoids in native producers, production in less widespread plants (i.e. specific liverwort species),
and lack of convergent synthetic routes capable of producing several analogs from one common intermediate.
Heterologous production of plant meroterpenoids has been accomplished in eukaryotic hosts (i.e. yeast) but
suffers from a pathway bottleneck caused by low catalytic activity and poor expression of plant prenyl cyclization
enzymes (e.g. THCA synthase). Bacterially derived cyclization enzymes that generate the same key
intermediate, an ortho-quinone methide, provide an attractive alternative for biocatalyst generation toward
production of plant-like meroterpenoids and their analogs. Here, I propose the development of new cyclization
biocatalysts engineered from bacterial biosynthetic enzymes for chemoenzymatic production of rare and
designer plant-like meroterpenoid products and their pharmacological evaluation to assess therapeutic promise.
This proposal aims to address issues of supply present for rare meroterpenoids with low accumulation in
native producers, generate novel, structurally diverse scaffolds using engineered biocatalysts, and test the
pharmacology (i.e. therapeutic promise) of such compounds. In Aim 1, I will engineer biosynthetic pathway
enzymes recently identified from the Moore lab, Clz9 and Tcz9, to chemoenzymatically produce meroterpenoids
with alternative regioselectivity and steric modification. While neuroactive meroterpenoids are predominantly
produced by flowering land plants, other species, like liverworts or marine bacteria, produce similar-looking
natural products. In Aim 2, I will identify new prenyl cyclase enzymes from marine bacteria and liverwort sources,
expanding the toolkit of biocatalysts for producing plant-like meroterpenoids, especially compounds with unique
stereochemistry and larger steric modifications. In Aim 3, produced compounds will be subjected to pre-
pharmacokinetics experiments to determine likely metabolic products, and both compounds and their metabolic
products will be assessed for ability to activate GPCR targets from the human brain. This research proposal will
produce rare and designer plant meroterpenoids using biocatalysts from bacterial hosts and identify which of the
produced analogs possess noteworthy therapeutic potential.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Anna Claire Love其他文献
Anna Claire Love的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
- 批准号:
10590611 - 财政年份:2022
- 资助金额:
$ 6.91万 - 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中的骨-脂肪相互作用
- 批准号:
10706006 - 财政年份:2022
- 资助金额:
$ 6.91万 - 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
- 批准号:
10368975 - 财政年份:2021
- 资助金额:
$ 6.91万 - 项目类别:
BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
- 批准号:
10365254 - 财政年份:2021
- 资助金额:
$ 6.91万 - 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
- 批准号:
10202896 - 财政年份:2021
- 资助金额:
$ 6.91万 - 项目类别:
BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
- 批准号:
10531570 - 财政年份:2021
- 资助金额:
$ 6.91万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10541847 - 财政年份:2019
- 资助金额:
$ 6.91万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10319573 - 财政年份:2019
- 资助金额:
$ 6.91万 - 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
- 批准号:
10062790 - 财政年份:2019
- 资助金额:
$ 6.91万 - 项目类别:
Promotion of NAD+ anabolism to promote lifespan
促进NAD合成代谢以延长寿命
- 批准号:
DE170100628 - 财政年份:2017
- 资助金额:
$ 6.91万 - 项目类别:
Discovery Early Career Researcher Award