Development of a Mirror-Image Natural Product as an Antiarrhythmic Therapeutic
开发镜像天然产物作为抗心律失常疗法
基本信息
- 批准号:10589858
- 负责人:
- 金额:$ 76.88万
- 依托单位:
- 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:2020-03-17 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccountingAdultAffinityAnimal Disease ModelsAnti-Arrhythmia AgentsArrhythmiaAtrial FibrillationBindingBiologicalBiologyCalciumCalorimetryCardiacCardiac MyocytesCatecholaminergic Polymorphic Ventricular TachycardiaCell surfaceCessation of lifeClinicalComplexConstitutionConstitutionalCritical PathwaysCryoelectron MicroscopyDataDepsipeptidesDevelopmentDiseaseDisease modelDockingDoseDrug IndustryEndowmentExhibitsFunctional disorderGenerationsGoalsHealthHumanHuman GeneticsHyperactivityImageImplantable DefibrillatorsIn VitroIon ChannelIonsLaboratoriesLeadMeasuresMediatingMembraneMethylationMolecularMusNatural ProductsNaturePathologicPatientsPeriodicityPharmaceutical PreparationsPharmacologyPharmacology StudyPropertyProteinsPublic HealthRegulationResearchResearch PersonnelRyR2SafetySarcoplasmic ReticulumStructureStructure-Activity RelationshipSyndromeTherapeuticTissuesTitrationsToxic effectVariantVentricular ArrhythmiaWorkanalogcandidate selectionchemical synthesisclinical candidateclinical developmentcostcrosslinkdesigndrug developmentdrug discoveryefficacy studyenantiomergain of function mutationhigh riskimprovedin silicoin vivoinhibitormortalitymouse modelnovelnovel therapeuticspharmacologicpre-clinicalpreclinical developmentprogramsrare conditionresponsesafety studysmall moleculestructural biologystructural determinantssuccesssudden cardiac deathtargeted treatmenttherapeutic developmenttherapeutic targettooltool development
项目摘要
Project Summary
This program focuses on the development of a new class of antiarrhythmic agents that inhibit
pathologically hyperactive RyR2, the calcium release channel in the sarcoplasmic reticulum
(intracellular) membrane. RyR2 is a validated therapeutic target in a human genetic arrhythmia
syndrome – Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). CPVT is caused by
gain of function mutations in RyR2. RyR2 hyperactivity has also been implicated mechanistically
in several other arrhythmia disorders, but RyR2-selective inhibitors are lacking. The overarching
goal of this transdisciplinary program is the selection of antiarrhythmic clinical candidates based
on the discovery that the enantiomer of the natural product verticilide (ent-verticilide) is a potent
inhibitor of RyR2-mediated calcium release in cardiomyocytes. Preliminary data from our
laboratories includes the discovery of ent-verticilide as a potent and (the first) selective inhibitor,
in contrast to its mirror-image, natural form. These tools have already shown an antiarrhythmic
effect in CPVT animal models of disease, thereby supporting the premise that selective
therapeutics can improve our understanding of RyR2 biology. Preliminary results are also founded
upon a de novo chemical synthesis of verticilide that provides both renewable access to drug, as
well as a platform for rapid analogue development, both in support of pharmacology studies. Aim
1 describes a broader program to explore ent-verticilide's biological activity and pharmacology, at
RyR2, in cardiomyocytes, and in mouse models of disease. The goal of Aim 2 is to prepare scores
of ent-verticilide analogues that further optimize potency while retaining selectivity. The premise
is that ent-verticilide is a powerful lead whose modularity will enable the development of a
molecular picture of structure-activity relationships despite the lack of a structural picture for RyR2
due to its size and complexity. A strength of this approach is its ability to adapt to changes in the
state of the art in RyR2 structural biology, an effort to which we will contribute as well (Aim 1).
Highly potent and selective compounds will be advanced in vivo for safety and efficacy studies in
Aim 3. This program is highly collaborative and transdisciplinary in nature, and the studies will
advance a novel class of compounds never-before-used in therapeutic development. Preliminary
results have already advanced our understanding of RyR2 molecular pharmacology, and promise
new antiarrhythmic agents to improve human health.
项目总结
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Structure-Activity Relationships for the N-Me- Versus N-H-Amide Modification to Macrocyclic ent-Verticilide Antiarrhythmics.
N-Me- 与 N-H-酰胺修饰对大环 ent-Verticilide 抗心律失常药的结构-活性关系。
- DOI:10.1021/acsmedchemlett.2c00377
- 发表时间:2022
- 期刊:
- 影响因子:4.2
- 作者:Smith,AbigailN;Thorpe,MadelaineP;Blackwell,DanielJ;Batiste,SuzanneM;Hopkins,CoreyR;Schley,NathanD;Knollmann,BjornC;Johnston,JeffreyN
- 通讯作者:Johnston,JeffreyN
ent -Verticilide B1 inhibits type 2 ryanodine receptor channels and is antiarrhythmic in Casq2-/- mice.
ent -Verticilide B1 抑制 2 型兰尼定受体通道,并在 Casq2-/- 小鼠中具有抗心律失常作用。
- DOI:10.1101/2023.07.03.547578
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Gochman,Aaron;Do,TriQ;Kim,Kyungsoo;Schwarz,JacobA;Thorpe,MadelaineP;Blackwell,DanielJ;Smith,AbigailN;Akers,WendellS;Cornea,RazvanL;Laver,DerekR;Johnston,JeffreyN;Knollmann,BjornC
- 通讯作者:Knollmann,BjornC
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Jeffrey Nicholas Johnston其他文献
Jeffrey Nicholas Johnston的其他文献
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{{ truncateString('Jeffrey Nicholas Johnston', 18)}}的其他基金
Development of a Mirror-Image Natural Product as an Antiarrhythmic Therapeutic
开发镜像天然产物作为抗心律失常疗法
- 批准号:
10372134 - 财政年份:2020
- 资助金额:
$ 76.88万 - 项目类别:
Development of a Mirror-Image Natural Product as an Antiarrhythmic Therapeutic
开发镜像天然产物作为抗心律失常疗法
- 批准号:
9917405 - 财政年份:2020
- 资助金额:
$ 76.88万 - 项目类别:
New Stereoselective Reactions for Chiral Amine Synthesis
手性胺合成的新立体选择性反应
- 批准号:
8110644 - 财政年份:2009
- 资助金额:
$ 76.88万 - 项目类别:
Enantioselective Functionalizations of Azomethines and Alkenes
甲亚胺和烯烃的对映选择性官能化
- 批准号:
9050686 - 财政年份:2009
- 资助金额:
$ 76.88万 - 项目类别:
Enantioselective Functionalizations of Azomethines and Alkenes
甲亚胺和烯烃的对映选择性官能化
- 批准号:
8697731 - 财政年份:2009
- 资助金额:
$ 76.88万 - 项目类别:
New Stereoselective Reactions for Chiral Amine Synthesis
手性胺合成的新立体选择性反应
- 批准号:
8267696 - 财政年份:2009
- 资助金额:
$ 76.88万 - 项目类别:
New Stereoselective Reactions for Chiral Amine Synthesis
手性胺合成的新立体选择性反应
- 批准号:
7817116 - 财政年份:2009
- 资助金额:
$ 76.88万 - 项目类别:
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