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Molecular pharmacology and physiology of kidney potassium transport

肾脏钾转运的分子药理学和生理学

基本信息

批准号：
8723159
负责人：
Jerod S. Denton
金额：
$ 25.71万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723159
关键词：
Affinity Amino Acids Animals Architecture Arrhythmia Atrial Fibrillation Binding Binding Sites Calcium Channel Cardiac Cations Cell physiology Computational Technique Development Disease Distal Diuresis Diuretics Drug Targeting Duct (organ) structure Edema Electrophysiology (science)GTP-Binding Proteins Hypertension KCNJ1 gene Kidney Lead Libraries Location Methods Molecular Molecular Models Molecular Probes Molecular Structure Mutagenesis Nephrons Nervous System Physiology Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Physiological Processes Physiology Play Potassium Potassium Channel Renal tubule structure Research Personnel Role Series Sodium Channel Structure Structure-Activity Relationship Techniques Testing Therapeutic Tissues Work analog cell type combinatorial chemistry counterscreen design follow-up high throughput screening in vivo inhibitor/antagonist insight large-conductance calcium-activated potassium channels molecular modeling novel patch clamp public health relevance research study response small molecule therapeutic target voltage

项目摘要

DESCRIPTION (provided by applicant): Inwardly rectifying potassium (Kir) channels are key regulators of diverse physiological processes and may represent novel drug targets for diseases. Their therapeutic potential has not been tested directly, however, due to the lack of drug-like compounds targeting inward rectifiers. The lack of selective "probes" has also hindered efforts to define the physiological functions of some Kir channels. To overcome this formidable barrier and create new opportunities for studying inward rectifier physiology, the investigators performed a high- throughput screen (HTS) of more than 200,000 compounds for small-molecule modulators of ROMK (Kir1.1), a putative target for a novel class of diuretic. One compound, termed VU590, inhibits ROMK at nanomolar concentrations and Kir7.1 in the low micromolar range, making it the first small-molecule inhibitor of both channels. The investigators went on to use medicinal chemistry to rationally design a nanomolar-affinity probe, termed VU591, which is highly selective for ROMK over more than 60 potential off targets, including inward rectifiers and BK channels. In Aim 1, the investigators will employ state-of-the-art molecular modeling techniques, atomic structure-guided mutagenesis and electrophysiology to define the VU590/591 binding sites in ROMK and Kir7.1. VU591 is remarkably selective for ROMK and therefore represents a promising candidate for further development for use in animal studies. In Aim 2, the investigators will first determine if VU591 is active in the native tissue by assessing its effects on K and Na transport in isolated perfused cortical collecting ducts under low- and high-flow conditions. The investigators also discovered a nanomolar-affinity inhibitor of a G-protein regulated inward rectifier (GIRK), a putative therapeutic target for atrial fibrillation. In Aim 3, the investigators will use medicinal chemistry, structure-guided mutagenesis and electrophysiology to define the molecular binding sites for this novel compound termed VU592. These studies will provide important new insights into the atomic structures of inward rectifiers and generate critically needed probes with which to define the integrative physiology and therapeutic potential of these channels. Lay summary: The investigators will combine medicinal chemistry, advanced computational techniques and classical physiological methods to develop drug-like compounds targeting potassium channels that could be therapeutic targets for hypertension, edema and cardiac arrhythmia.

描述（由申请人提供）：抑制整流钾（Kir）通道是多种生理过程的关键调节剂，可能代表疾病的新型药物靶点。然而，由于缺乏靶向内向整流器的药物样化合物，它们的治疗潜力尚未被直接测试。缺乏选择性“探针”也阻碍了确定某些Kir通道的生理功能的努力。为了克服这一巨大的障碍并为研究内向整流生理学创造新的机会，研究人员对ROMK（Kir1.1）的小分子调节剂进行了20多万种化合物的高通量筛选（HTS），ROMK是一类新型利尿剂的推定靶点。一种名为VU 590的化合物在纳摩尔浓度下抑制ROMK，在低微摩尔范围内抑制Kir7.1，使其成为这两种通道的第一种小分子抑制剂。研究人员继续使用药物化学来合理设计一种称为VU 591的纳摩尔亲和探针，该探针对ROMK具有高度选择性，超过60种潜在的脱靶点，包括内向整流器和BK通道。在目标1中，研究人员将采用最先进的分子建模技术，原子结构指导的诱变和电生理学来确定ROMK和Kir7.1中的VU 590/591结合位点。VU 591对ROMK具有显著的选择性，因此代表了进一步开发用于动物研究的有希望的候选者。在目标2中，研究人员将首先通过评估VU 591在低流量和高流量条件下对分离的灌注皮质集合管中K和Na转运的影响来确定VU 591是否在天然组织中具有活性。研究人员还发现了一种G蛋白调节的内向整流器（GIRK）的纳摩尔亲和力抑制剂，这是房颤的一个假定治疗靶点。在目标3中，研究人员将使用药物化学，结构导向诱变和电生理学来定义这种称为VU 592的新型化合物的分子结合位点。这些研究将为内向整流器的原子结构提供重要的新见解，并产生急需的探针，以确定这些通道的综合生理学和治疗潜力。敷设总结：研究人员将结合联合收割机药物化学，先进的计算技术和经典的生理学方法，开发针对钾通道的药物样化合物，这些化合物可能成为高血压，水肿和心律失常的治疗靶点。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery and characterization of a potent and selective inhibitor of Aedes aegypti inward rectifier potassium channels.

DOI：
10.1371/journal.pone.0110772
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Raphemot R;Rouhier MF;Swale DR;Days E;Weaver CD;Lovell KM;Konkel LC;Engers DW;Bollinger SR;Hopkins C;Piermarini PM;Denton JS
通讯作者：
Denton JS

Eliciting renal failure in mosquitoes with a small-molecule inhibitor of inward-rectifying potassium channels.

DOI：
10.1371/journal.pone.0064905
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Raphemot R;Rouhier MF;Hopkins CR;Gogliotti RD;Lovell KM;Hine RM;Ghosalkar D;Longo A;Beyenbach KW;Denton JS;Piermarini PM
通讯作者：
Piermarini PM

Druggability of the inward rectifier family: a hope for rare channelopathies?

内向整流器家族的成药性：罕见通道病的希望？

DOI：
10.4155/fmc.14.12
发表时间：
2014
期刊：
Future medicinal chemistry
影响因子：
4.2
作者：
Denton,JerodS
通讯作者：
Denton,JerodS

Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics.

DOI：
10.1016/j.coph.2013.11.002
发表时间：
2014-04
期刊：
Current opinion in pharmacology
影响因子：
4
作者：
Swale DR;Kharade SV;Denton JS
通讯作者：
Denton JS

Excretion of NaCl and KCl loads in mosquitoes. 2. Effects of the small molecule Kir channel modulator VU573 and its inactive analog VU342.

蚊子体内 NaCl 和 KCl 负荷的排泄。

DOI：
10.1152/ajpregu.00106.2014
发表时间：
2014
期刊：
American journal of physiology. Regulatory, integrative and comparative physiology
影响因子：
0
作者：
Rouhier,MatthewF;Hine,RebeccaM;Park,SeokhwanTerry;Raphemot,Rene;Denton,Jerod;Piermarini,PeterM;Beyenbach,KlausW
通讯作者：
Beyenbach,KlausW

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Jerod S. Denton其他文献

A LRRC8 chimera with native functional properties is a heptamer with a large lipid-blocked pore

DOI：
10.1016/j.bpj.2022.11.2466
发表时间：
2023-02-10
期刊：
Conference abstract
影响因子：
作者：
Hirohide Takahashi;Toshiki Yamada;Jerod S. Denton;Kevin Strange;Erkan Karakas
通讯作者：
Erkan Karakas

55: Rational Synthesis of a Selective Renal Outer Medullary Potassium Channel (ROMK) Antagonist

DOI：
10.1053/j.ajkd.2010.02.062
发表时间：
2010-04-01
期刊：
Conference abstract
影响因子：
作者：
Gautam Bhave;Brian A. Chauder;Rishin Kadakia;Eric S. Dawson;Craig W. Lindsley;C. David Weaver;Jerod S. Denton
通讯作者：
Jerod S. Denton

Development of Small-Molecule Inhibitors of Proton-Activated Chloride Channels

DOI：
10.1016/j.bpj.2019.11.3197
发表时间：
2020-02-07
期刊：
Conference abstract
影响因子：
作者：
Eric E. Figueroa;Jerod S. Denton
通讯作者：
Jerod S. Denton

Oligomeric structure of LRRC8/VRAC channels: Arguments for a heptameric conformation

DOI：
10.1016/j.bpj.2022.11.789
发表时间：
2023-02-10
期刊：
Conference abstract
影响因子：
作者：
Jerod S. Denton;Toshiki Yamada;Hirohide Takahashi;Erkan Karakas;Kevin Strange
通讯作者：
Kevin Strange