MOLECULES
·
2023
·Vol. 28
·期 13
·5176
·
IF 4.6
Dongrong Cheng,Xiaofeng Wei,Yanting Zhang,Qian Zhang,Jianwei Xu,Jiaxin Yang,Junjie Yu,Antony Stalin,Huan Liu,Jintao Wang,Dian Zhong,Lanying Pan,Wei Zhao,Yuan Chen
Erythromycin is one of the few compounds that remarkably increase ether-a-go-go-related gene (hERG) inhibition from room temperature (RT) to physiological temperature (PT). Understanding how erythromycin inhibits the hERG could help us to decide which compounds are needed for further studies. The whole-cell patch clamp technique was used to investigate the effects of erythromycin on hERG channels at different temperatures. While erythromycin caused a concentration-dependent inhibition of cardiac hERG channels, it also shifted the steady-state activation and steady-state inactivation of the channel to the left and significantly accelerated the onset of inactivation at both temperatures, although temperature itself caused a profound change in the dynamics of hERG channels. Our data also suggest that the binding pattern to S6 of the channels changes at PT. In contrast, cisapride, a well-known hERG blocker whose inhibition is not affected by temperature, does not change its critical binding sites after the temperature is raised to PT. Our data suggest that erythromycin is unique and that the shift in hERG inhibition may not apply to other compounds.Keywords:erythromycin;temperature;hERG;steady-state activation;steady-state inactivation
研究领域:
药理学
·
心脏病学
·
生物物理学
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DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2014
·Vol. 387
·期 11
·1079-1089
·
IF 2.36
Zhao Xin,Zhang Kai-ping,Huang Ting,Yan Cai-Chuan,Liu Li-Rong,Zhu Qi-Lei,Guo Feng-Feng,Liu Chen,Li Bao-Xin
Arsenic trioxide (As 2 O 3 ) is used to treat acute promyelocytic leukemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As 2 O 3 can damage the human ether-a-go-go-related gene (hERG) current via disturbing its trafficking to cellular membrane. This study aimed to investigate whether the As 2 O 3 -insulted hERG channel can be rescued by resveratrol, a recognized cardioprotective agent. The whole-cell patch clamp technique was used to record the hERG current and action potential duration. Co-immunoprecipitation and Western blot assay were applied to determine the function of hERG-Hsp70/Hsp90 chaperone complexes and the expression alteration of protein-folding-related proteins, respectively. Compared with treatment of As 2 O 3 alone, co-treatment with resveratrol successfully restored the current and surface expression of hERG and obviously shortened action potential duration in guinea pig ventricular myocytes. Further experiments demonstrate that resveratrol relieved As 2 O 3 -caused endoplasmic reticulum (ER) stress by restoring the function of hERG-Hsp70/Hsp90 chaperone complexes and downregulating the protein expression of ER chaperone proteins (calnexin and calreticulin) and activating transcription factor 6. In conclusion, resveratrol was able to rescue the trafficking deficiency and relieve the ER stress (ERS). Our findings suggest that resveratrol has a potential effect to alleviate the adverse effect of As 2 O 3 on cardiotoxicity.
研究领域:
药理学
·
毒理学
·
心脏病学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2019
·
IF 6.054
Xiaowu Dong,Wenhu Zhan,Mengting Zhao,Jinxin Che,Xiaoyang Dai,Yizhe Wu,Lei Xu,Yubo Zhou,Yanmei Zhao,Tian Tian,Gang Cheng,Zegao Jin,Jia Li,Yanfei Shao,Qiaojun He,Bo Yang,Qinjie Weng,Yongzhou Hu
A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, A12, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure–activity relationship of compound A12, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Akt1 and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.
研究领域:
药物化学
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肿瘤学
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药物研发
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分子生物学
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DOI
PubMed
高影响因子
TALANTA
·
2022
·
IF 6.556
Wen-Shu Zhang,Xiao-Peng Liu,Shuai Yue,Ya-Ning Wang,Yue Wang,Zhang-Run Xu
Research on ion channels and their monoclonal antibodies plays a critical role in drug development and disease diagnosis. The current ion channel researches are often not conducted in the microenvironment for cells survival , which restricts the mechanism study of the links between the cell structure and the ion channel function. In this work, we synthesized gold core-4-mercaptobenzonitrile-sliver shell-goat anti-rabbit immunoglobulin G ( [email protected] @ [email protected] ) nanoparticles as surface-enhanced Raman scattering (SERS) nanoprobes for investigating the human ether-a-go-go related gene (hERG) potassium ion channel in cell membranes. This is the first attempt to study ion channels using SERS. Due to the unique core-molecule-shell structure and the silver shell of nanoprobes, strong and stable SERS signal was obtained. With the help of antibodies, the [email protected] @ [email protected] nanoprobes were captured by hERG antibodies and then bonded with hERG ion channels based on the sandwich immune response. The reporter molecule, 4-MBN, displayed a strong and sharp characteristic peak at 2233 cm - 1 in the Raman silent region. The intensity of this peak denoted the concentration of antibodies and the expression of ion channel proteins. We successfully applied this amplification-free method for in-situ imaging the distribution of the hERG ion channel on the transfected HEK293 cell surface at the single-cell level. This hERG ion channel profiling strategy promises a maneuverable tool for ion channel research.
研究领域:
生物物理学
·
纳米技术
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分析化学
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细胞生物学
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2015
·
IF 3.028
Meng Yan,Kaiping Zhang,Yanhui Shi,Lifang Feng,Lin Lv,Baoxin Li
Berberine (BBR), an isoquinoline alkaloid mainly isolated from plants of Berberidaceae family, is extensively used to treat gastrointestinal infections in clinics. It has been reported that BBR can block human ether-a-go-go-related gene ( hERG ) potassium channel and inhibit its membrane expression. The hERG channel plays crucial role in cardiac repolarization and is the target of diverse proarrhythmic drugs. Dysfunction of hERG channel can cause long QT syndrome. However, the regulatory mechanisms of BBR effects on hERG at cell membrane level remain unknown. This study was designed to investigate in detail how BBR decreased hERG expression on cell surface and further explore its pharmacological rescue strategies. In this study, BBR decreases caveolin-1 expression in a concentration-dependent manner in human embryonic kidney 293 (HEK293) cells stably expressing hERG channel. Knocking down the basal expression of caveolin-1 alleviates BBR-induced hERG reduction. In addition, we found that aromatic tyrosine (Tyr652) and phenylalanine (Phe656) in S6 domain mediate the long-term effect of BBR on hERG by using mutation techniques. Considering both our previous and present work, we propose that BBR reduces hERG membrane stability with multiple mechanisms. Furthermore, we found that fexofenadine and resveratrol shorten action potential duration prolongated by BBR, thus having the potential effects of alleviating the cardiotoxicity of BBR.
研究领域:
药理学
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心脏病学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
·
2022
·Vol. 80
·期 5
·679-689
·
IF 3.271
Wang Na,Yang Yang,Wen Jing,Fan Xin-Rong,Li Jian,Xiong Bing,Zhang Jin,Zeng Bo,Shen Jian-Wu,Chen Gui-Lan
Tolterodine is a first-line antimuscarinic drug used to treat overactive bladder. Adverse cardiac effects including tachycardia and palpitations have been observed, presumably because of its inhibition of the Human Ether-à-go-go-Related gene (hERG) K+ channel.
However, the molecular mechanism of hERG channel inhibition by tolterodine is largely unclear. In this study, we performed molecular docking to identify potential binding sites of tolterodine in hERG channel, and two-microelectrode voltage-clamp to record the currents of hERG and its mutants
expressed in Xenopus oocytes. The results of computational modeling demonstrated that phenylalanine at position 656 (F656) and tyrosine at position 652 (Y652) on the S6 helix of hERG channel are the most favorable binding residues of tolterodine, which was validated by electrophysiological
recordings on Y652A and F656A hERG mutants. The Y652A and F656A mutations decreased inhibitory potency of tolterodine 345-fold and 126-fold, respectively. The Y652A mutation significantly altered the voltage dependence of channel inhibition by tolterodine. For both the wild-type and the mutant
channels, tolterodine reduced the currents in a time-dependent manner, and the blockade occurred with the channel activated. Tolterodine did not interfere with hERG channel deactivation, whereas channel inactivation greatly impaired its blocking effect. The inhibition of hERG channel by tolterodine
is independent of its action on muscarinic acetylcholine receptors. In conclusion, tolterodine is an open-state blocker of hERG K+ channel with nanomolar potency. Y652 and F656, 2 aromatic residues on the inner S6 helix, are responsible for the high-affinity binding of tolterodine
to hERG channel.
研究领域:
药理学
·
分子生物学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Ying Xun Zhou,Wen Ping Wang,Jin Ke,Hui Ping Ou,Lin Yun Chen,An Guo Hou,Peng Li,Yun Shu Ma,Wen Bin Jin
Dysfunction of the Nav1.5, Cav1.2, and Kv channels could interfere with the AP and result in arrhythmias and even heart failure. We herein present a novel library of nuciferine analogs that target ion channels for the treatment of arrhythmias. Patch clamp measurements of ventricular myocytes revealed that 6a dramatically blocked both the I Na and I Ca without altering the current voltage relationship (including the activation potential and peak potential), accelerated the inactivation of Nav and Cav channels and delayed the resurrection of these channels after inactivation. Additionally, 6a significantly decreased the APA and RMP without affecting the APD30 or APD50. The IC 50 values of 6a against Nav1.5 and Cav1.2 were 4.98 μM and 4.62 μM, respectively. Furthermore, 6a (10 μM) blocked I Ks , I K1 , and I to with values of 17.01 %±2.54 %, 9.09 %±2.78 %, and 11.15 %±3.52 %, respectively. Surprisingly, 6a weakly inhibited hERG channels, suggesting a low risk of proarrhythmia. The cytotoxicity evaluation of 6a with the H9c2 cell line indicated that this compound was noncytotoxic. In vivo studies suggested that these novel nuciferine analogs could shorten the time of arrhythmia continuum induced by BaCl 2 and normalize the HR, QRS, QT and QTc interval and the R wave amplitude. Moreover, 6a dose-dependently affected aconitine-induced arrhythmias and notably improved the cumulative dosage of aconitine required to evoke VP, VT, VF and CA in rats with aconitine-induced arrhythmia. In conclusion, nuciferine analogs could be promising ion channel blockers that could be further developed into antiarrhythmic agents.
研究领域:
药理学
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心血管病学
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分子生物学
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Xie-Huang Sheng,Lin-Song Teng,Xin-Hui Wang,Li-Qi Jiang,Xue-Cheng Sun,Jin-Long Mao,Lei Zhang
Cardiovascular diseases arise from intertwined cell-death and stress-response pathways, underscoring the need for therapeutics that extend beyond single-target mechanisms. Seeking drug-repurposing opportunities within existing cardiovascular agents, we screened clinically explored compounds for unrecognized cytoprotective activity and identified the hERG/Kv11.1 activator NS-1643—originally developed as an antiarrhythmic candidate—as a potent ferroptosis inhibitor. NS-1643 broadly suppressed GPX4 inhibitor–induced ferroptotic death across diverse cell types, whereas other hERG modulators were inactive, and neither pharmacologic blockade nor genetic silencing of hERG altered its efficacy, demonstrating that its protective mechanism is independent of ion-channel modulation. Mechanistic profiling showed that NS-1643 does not restore canonical ferroptosis-defense systems, but instead operates as a direct lipid-peroxyl radical trapper, supported by radical-scavenging assays and density functional theory revealing an energetically favorable hydrogen-atom transfer mediated by its ortho-amino–phenolic motif. In a murine model of doxorubicin (DOX) cardiotoxicity, NS-1643 markedly improved survival, preserved systolic performance, and reduced myocardial injury, fibrosis, and 4-HNE accumulation, whereas the comparator hERG agonist NS-3623 conferred no benefit. These findings reposition NS-1643 as a dual-mechanism, ferroptosis-targeting cardioprotective agent and illustrate how drug repurposing can reveal multi-target therapeutic potential within existing cardiovascular chemical space, offering a promising strategy to mitigate anthracycline-induced cardiac injury.
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PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2021
·Vol. 43
·期 1
·121-132
·
IF 6.15
Zhao Ze-an,Jiang Yu,Chen Yan-yu,Wu Ting,Lan Qun-sheng,Li Yong-mei,Li Lu,Yang Yang,Lin Cui-ting,Cao Ying,Zhou Ping-zheng,Guo Jia-yin,Tian Yuan-xin,Pang Jian-xin
Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo. We showed that CDER167 exerted dual-target inhibitory effects on both URAT1 and GLUT9: CDER167 concentration-dependently inhibited the uptake of [ 14 C]-uric acid in URAT1-expressing HEK293 cells with an IC 50 value of 2.08 ± 0.31 μM, which was similar to that of RDEA3170 (its IC 50 value was 1.47 ± 0.23 μM). Using site-directed mutagenesis, we demonstrated that CDER167 might interact with URAT1 at S35 and F365. In GLUT9-expressing HEK293T cells, CDER167 concentration-dependently inhibited GLUT9 with an IC 50 value of 91.55 ± 15.28 μM, whereas RDEA3170 at 100 μM had no effect on GLUT9. In potassium oxonate-induced hyperuricemic mice, oral administration of CDER167 (10 mg·kg −1 · d −1 ) for 7 days was more effective in lowering uric acid in blood and significantly promoted uric acid excretion in urine as compared with RDEA3170 (20 mg·kg −1 · d −1 ) administered. The animal experiment proved the safety of CDER167. In addition, CDER167 displayed better bioavailability than RDEA3170, better metabolic stability and no hERG toxicity at 100 μM. These results suggest that CDER167 deserves further investigation as a candidate antihyperuricemic drug targeting URAT1 and GLUT9.
研究领域:
药理学
·
医学
·
药物开发
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Zhanpan Wu,Wenping Wang,Chunyan Yang,Lin Peng,Siying Yang,Qiaofeng Yan,Wenbin Jin
This study identified 6–24, a novel antiarrhythmic lead derived from the roemerine scaffold, which exhibited a distinctive multichannel blockade profile targeting Nav1.5 and Cav1.2, while demonstrating only weak inhibition of hERG. This gentle multitarget profile avoided excessive single-channel blockade associated with proarrhythmic drugs, conferring low QT prolongation risk, a key advantage over agents like verapamil. Patch-clamp and iPSC-cardiomyocyte MEA confirmed prolonged action potentials and reduced conduction velocity. Multielectrode mapping in isolated hearts further revealed that the compound dose-dependently prolonged ventricular activation time and reduced conduction velocity, accompanied by a decrease in the heart rate, without significantly altering the QTc interval. Pharmacokinetic analysis further established that this active concentration could be achieved clinically. Beyond electrophysiological modulation, 6–24 uniquely restored cardiac function in vivo, normalizing ventricular dimensions and hemodynamics. With integrated efficacy, safety, and functional restoration, 6–24 represented a promising multitarget candidate for ventricular arrhythmia therapy.
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Ruoqing Zeng,Meimiao Fang,Ancheng Shen,Xiaolei Chai,Yumiao Zhao,Mingyao Liu,Lingfeng Zhu,Weiwei Rui,Bo Feng,Liang Hong,Chunyong Ding,Zilan Song,Weiqiang Lu,Ao Zhang
Accumulating evidence has demonstrated a critical pathological role of oxysterol receptor GPR183 in various inflammatory and autoimmune diseases, including inflammatory bowel disease (IBD). However, the currently reported GPR183 antagonists are very limited and not qualified for in vivo studies due to their inferior druglike properties. Herein, we conducted a structural elaboration focusing on improving its PK and safety profile based on a reference antagonist NIBR189. Of note, compound 33, bearing an aminobenzothiazole motif, exhibited reduced hERG inhibition, improved PK properties, and robust antagonistic activity (IC50 = 0.82 nM) with high selectivity against GPR183. Moreover, compound 33 displayed strong in vitro antimigration and anti-inflammatory activity in monocytes. Oral administration of compound 33 effectively improved the pathological symptoms of DSS-induced experimental colitis. All of these findings demonstrate that compound 33 is a novel and promising GPR183 antagonist suitable for further investigation to treat IBD.
研究领域:
药理学
·
免疫学
·
药物化学
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DOI
PubMed
高影响因子
TOXICOLOGY
·
2024
·
IF 4.8
Wenting Wu,Jinglei Sun,Jiali Zhang,Haining Zhao,Suhua Qiu,Congxin Li,Chenxia Shi,Yanfang Xu
The use of tyrosine kinase inhibitors (TKIs) has resulted in significant occurrence of arrhythmias. However, the precise mechanism of the proarrhythmic effect is not fully understood. In this study, we found that nilotinib (NIL), vandetanib (VAN), and mobocertinib (MOB) induced the development of “cellrhythmia” (arrhythmia-like events) in a concentration-dependent manner in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Continuous administration of NIL, VAN, or MOB in animals significantly prolonged the action potential durations (APD) and increased susceptibility to arrhythmias. Using phosphoproteomic analysis, we identified proteins with altered phosphorylation levels after treatment with 3 μM NIL, VAN, and MOB for 1.5 h. Using these identified proteins as substrates, we performed kinase–substrate enrichment analysis to identify the kinases driving the changes in phosphorylation levels of these proteins. MAPK and WNK were both inhibited by NIL, VAN, and MOB. A selective inhibitor of WNK1, WNK-IN-11, induced concentration- and time-dependent cellrhythmias and prolonged field potential duration (FPD) in hiPSC-CMs in vitro; furthermore, administration in guinea pigs confirmed that WNK-IN-11 prolonged ventricular repolarization and increased susceptibility to arrhythmias. Fingding indicated that WNK1 inhibition had an in vivo and in vitro arrhythmogenic phenotype similar to TKIs. Additionally,three of TKIs reduced hERG and KCNQ1 expression at protein level, not at transcription level. Similarly, the knockdown of WNK1 decreased hERG and KCNQ1 protein expression in hiPSC-CMs. Collectively, our data suggest that the proarrhythmic effects of NIL, VAN, and MOB occur through a kinase inhibition mechanism. NIL, VAN, and MOB inhibit WNK1 kinase, leading to a decrease in hERG and KCNQ1 protein expression, thereby prolonging action potential repolarization and consequently cause arrhythmias.
研究领域:
心脏病学
·
药理学
·
蛋白质组学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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