Biocatalytic approaches to antiepileptic drug targets

抗癫痫药物靶标的生物催化方法

基本信息

批准号：
9922670
负责人：
April Lukowski
金额：
$ 1.2万
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：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922670
关键词：
Action Potentials Affinity Anabolism Antiepileptic Agents Architecture Arrhythmia Binding Biochemical Biological Assay Brain Breathing Cardiac Chemicals Chemistry Childhood Climacteric Complex Cyanobacterium Development Disease Dose Drug Design Drug Targeting Electrophysiology (science)Enzymes Epilepsy Family Gene Cluster Generations Genes Guanidines Human Human body Hydroxylation Individual Lead Ligands Mediating Methods Molecular Mus Mutate Mutation Myotonia Natural Products Nature Neuraxis Neurons Paralysed Pathway interactions Patients Pattern Positioning Attribute Protein Isoforms Rattus Reaction Reporting Research Route Sampling Saxitoxin Shellfish Signal Transduction Skeletal Muscle Sodium Channel Sodium Channel Binding Sodium Channel Blockers Source Specificity Sulfate Techniques Toxin Variant Work analog base chemical reaction design dravet syndrome drug market enzyme substrate epileptic encephalopathies functional group gonyautoxins hydroxyl group novel oxidation response scaffold side effect skeletal small molecule student mentoring sulfotransferase voltage

项目摘要

Proposal Summary Discovering small molecule ligands with a high affinity for voltage-gated sodium channels and specificity for disease relevant isoforms is challenging. Common synthetic strategies require prefunctionalization to introduce heteroatoms and larger functional groups, rendering the molecules difficult to handle, purify, and subject to further diversification. Nature approaches such synthetic bottlenecks by constructing simple cores and decorating scaffolds later on in biosynthesis. Chemists take inspiration from Nature’s techniques in designing late-stage C–H functionalization routes, but the ability of enzymes to generate molecular complexity is unmatched by state-of-the-art synthetic methods. Thus, biocatalysis represents a unique approach to tackling the synthetic challenges associated with drug design. Paralytic shellfish toxins (PSTs) are an untapped source of antiepileptic drug targets. Over 50 naturally derived PSTs have been identified, and the select few that have been assessed for binding to voltage-gated sodium channels (VGSCs) have demonstrated the ability to block VGSCs. This molecular response corresponds to physical responses desired in antiepileptic drug targets. The study of PSTs as antiepileptic drug targets has been hindered by challenging synthetic routes and the inability to isolate sufficient quantities of most of the >50 analogs. Gene clusters associated with paralytic shellfish toxin biosynthesis have been identified, enabling opportunities to leverage enzymes capable of chemistry inaccessible to even the most skilled chemist. This proposal describes strategies to elucidate the paralytic shellfish toxin biosynthetic pathway, evaluate enzyme substrate scopes, and isolate novel compounds from biocatalytic reactions for analysis with VGSCs using electrophysiological techniques. In summary, this work aims to diversify the PST scaffold using PST biosynthetic enzymes from cyanobacteria, enabling chemical transformations on complex, heteroatom-rich molecules that are otherwise intractable. The methods established in this proposal will accelerate the discovery of new antiepileptic drugs by developing new chemical reactions using biocatalysts from the biosynthetic pathway of known VGSC blocking compounds.

提案摘要发现对电压门控钠通道具有高亲和力的小分子配体，特异性疾病相关的同工型具有挑战性。杂原子和较大的官能团，使分子difficalt处理，并受到进一步的多样化。稍后在生物合成中装饰脚手架。晚期熟由最新的合成方法无与伦比。与药物设计相关的合成挑战。瘫痪的贝类毒素（PST）是未开发的抗癫痫药物的来源。 PST已被构成，并且评估了与电压门控钠结合的精选的少数通道（VGSC）已经证明了阻止的能力抗癫痫药物的物理反应是对PSTS的研究。受到挑战的合成路线和隔离> 50> 50的可比性量的无效性的阻碍类似物。甚至最熟练的化学家都无法获得化学能力的酶。提案描述了阐明麻痹性贝类毒素生物合成途径的策略，评估酶底物示波器和分离出从生物催化反应的新型化合物，用于使用VGSC进行分析电生理技术。总而言之，这项工作旨在使用来自蓝细菌的PST生物合成酶多样化PST支架，在复合物，富含杂种的分子上实现化学转化，原本是棘手的在本提案中建立的方法，通过开发新的新抗脑电图，加速发现新的抗脑电皮药物使用来自已知VGSC阻断化合物的生物合成途径的生物催化剂的化学反应。