基于G-蛋白偶联受体激酶2抑制剂治疗心力衰竭的合理药物设计（英文）  

Rational design of GRK2 inhibitors for the treatment of heart failure

作　　者：John J TESMER Helen V WALDSCHMIDT Marie C CATO Renee BOULEY Osvaldo CRUZ-RODRIGUEZ Scott D LARSEN 

机构地区：[1]University of Michigan Life Sciences Institute, Ann ArborMichigan 48109 USA [2]Department of Biological Sciences, Purdue University,West Lafayette Indiana 47907 USA [3]University of Michigan Valteich Medicinal Chemistry Core, Ann ArborMichigan 48109 USA

出　　处：《中国药理学与毒理学杂志》2017年第10期945-946,共2页Chinese Journal of Pharmacology and Toxicology

基　　金：supported by National Institutes of Health(NIH)grants HL071818,HL086865,and HL122416(to JT);American Heart Association grant 15PRE22730028(to HW);JT and SL were supported by grants from the Center for Discovery of New Medicine,University of Michigan;MCC and OC acknowledge training grant support from the University of Michigan Chemistry Biology Interface training program(NIH grant 5T32GM008597)

摘　　要：G protein-coupled receptors(GPCRs)convert extracellular stimuli in the form of hormones,odorants and light into profound changes in cell homeostasis.Their timely desensitization is critical for cells to rapidly respond to changes in their environment and to avoid damage from sustained signaling.Seven GPCR kinases(GRKs)phosphorylate and regulate the activity of most of the^800 GPCRs in the human genome.Although GRKs normally play an adaptive role,in conditions such as chronic heart failure they are overexpressed and linked to disease progression.GRK2 and GRK5 have thus become important targets for the treatment of heart failure and pathological cardiac hypertrophy,respectively.Our lab has determined atomic structures representing all three vertebrate GRK subfamilies,and is now in the midst of a campaign to develop selective inhibitors of these enzymes using structure-based rational design.We have identified the FDA approved drug paroxetine as a selective GRK2 inhibitor,determined the crystal structure of the GRK2·paroxetine complex and,in collaboration with the Koch lab,showed that the drug improves contractility in myocytes and,most impressively,recovery in postmyocardial infarcted mice.Since then,we have identified additional chemical scaffolds that exhibit even higher potency and/or selectivity for GRK5.Using a"hybrid"inhibitor design approach we have generated GRK selective chemical probes that exhibit improved potency and stability and are able to increase inotropy and dampen the hypertrophic response in cardiomyocytes and small animal models.Structural analysis has revealed the molecular basis for selectivity and potency in many of these compounds,allowing for the design of future generations of GRK chemical probes.G protein-coupled receptors（GPCRs）convert extracellular stimuli in the form of hormones,odorants and light into profound changes in cell homeostasis.Their timely desensitization is critical for cells to rapidly respond to changes in their environment and to avoid damage from sustained signaling.Seven GPCR kinases（GRKs）phosphorylate and regulate the activity of most of the^800 GPCRs in the human genome.Although GRKs normally play an adaptive role,in conditions such as chronic heart failure they are overexpressed and linked to disease progression.GRK2 and GRK5 have thus become important targets for the treatment of heart failure and pathological cardiac hypertrophy,respectively.Our lab has determined atomic structures representing all three vertebrate GRK subfamilies,and is now in the midst of a campaign to develop selective inhibitors of these enzymes using structure-based rational design.We have identified the FDA approved drug paroxetine as a selective GRK2 inhibitor,determined the crystal structure of the GRK2·paroxetine complex and,in collaboration with the Koch lab,showed that the drug improves contractility in myocytes and,most impressively,recovery in postmyocardial infarcted mice.Since then,we have identified additional chemical scaffolds that exhibit even higher potency and/or selectivity for GRK5.Using a＂hybrid＂inhibitor design approach we have generated GRK selective chemical probes that exhibit improved potency and stability and are able to increase inotropy and dampen the hypertrophic response in cardiomyocytes and small animal models.Structural analysis has revealed the molecular basis for selectivity and potency in many of these compounds,allowing for the design of future generations of GRK chemical probes.

关 键 词：herat failure GPCR GPCR kinase PAROXETINE drug design X-ray crystallography 

分 类 号：R91[医药卫生—药学]