Select publications by professor terry campbell unsw. Jul 01, 2003 read blockade of herg potassium currents by fluvoxamine. The toxic arsenals of venomous organisms contain polypeptide toxins that block ion channels to enable the rapid paralysis of a potential prey or foe. As highlighted by a recent spotlight issue of cardiovascular research, the existence of major differences between men and women in the function and pathophysiology of the cardiovascular system implicates the need for genderspecific optimisation of patient treatment. This paper presents an assessment of the druglikeness and pharmacokinetic profile of 2,400 compounds of natural origin, currently available in the recently published streptomedb database. Erythromycin is a macrolide antibiotic that is widely used for various infections of the upper respiratory tract, skin, and soft tissue. Herg current increased during repolarization to reach a maximum amplitude during phases 2 and 3 of the cardiac action potential. Campbell tj, 1999, perhexiline maleate inhibits the rapidly activating cardiac delayed rectifier potassium channel ikr in rabbit ventricular myocytes and the human etheragogorelated gene herg potassium current, in australian and new zealand journal of medicine, adis international limited, perth. Association of gammasecretase with lipid rafts in postgolgi and endosome membranes. Escitalopram block of herg potassium channels springerlink. Vetrivel ks, cheng h, lin w, sakurai t, li t, nukina n, wong pc, xu h, thinakaran g. Dec 01, 2001 1 the unusual kinetics of human ether. Another scorpion toxin iberiotoxin is selective for bk channel k ca 1.
Inhibition of the current of heterologously expressed herg. Inhibition of the human etheragogorelated gene herg potassium channel by cisapride, affinity for open and inactivated states. Micromolar bepridil inhibited tail currents carried by kcnq1kcne1 channels in a concentrationdependent manner ic50 5. Threedimensional molecular models were generated for antimalarial compounds of african origin from weakly active to. Role of the cytosolic chaperones hsp70 and hsp90 in. Jan 24, 2020 in other words the position of f627 in herg t and herg ts is anomalous in the context of other k v channels and herg ts s631a that have more limited inactivation properties, leading to the suggestion that herg t and herg ts represents an inactivated state as would be expected in the absence of a membrane potential i. Frontiers an update on the structure of herg pharmacology. The objectives of this study were i to identify and characterise any inhibitory action on herg of the selective. Herg current increased during repolarization to reach a maximum amplitude during phases 2.
Herg potassium channels are constitutively expressed in. The human etheragogorelated gene herg, kcnh2, encodes the. Identification of a proton sensor that regulates conductance. The q9e kcne2 mutation increases the potency of clarithromycins action on herg abbott et al. Insights into the molecular mechanism of herg1 channel activation and blockade by drugs. The kcne2 protein can complex with herg and is a putative molecular partner for herg in forming i kr channels abbott et al. Blockade of herg potassium currents by fluvoxamine british.
Relationships between preclinical cardiac electrophysiology. Mutations in herg lead to the congenital long qt syndrome type 2 associated with increased risks of ventricular arrhythmogenesis and sudden cardiac death 7, 34. Friend and foe, trends in pharmacological sciences, vol. Although herg currents have been studied extensively, little is known about the proteins involved in maturation and trafficking of herg. Expression and function of kcnh2 herg in the human jejunum. State dependent dissociation of herg channel inhibitors. The delicate synchronization of cardiac ion channels underlies the spread of cardiac electrical excitation. Malaria is an endemic disease affecting many countries in tropical regions. When we used an action potential clamp technique, herg current activation began shortly after the upstroke of the action potential waveform. Second messenger modulation of the human ether a gogo. Drug regulatory authorities have become increasingly concerned about these potentially lethal sideeffects, particularly for noncardiac drugs. Structural determinants of herg channel block by clofilium and ibutilide article pdf available in molecular pharmacology 662. A mutation in the pore region of herg k channels expressed in xenopus.
We attempt to evaluate the druglikeness of a collection of. Herg k channels activation during plintegrinmediated adhesion to fibronectin induces an upregulaton of avpl integrin in the prosteoclastic leukemia cell line flg 29. Modification by kcne1 variants of the herg potassium channel. When the effect of the drug was examined with a short test pulse protocol 250 milliseconds, ic50 became twofold smaller than that measured with milliseconds test pulse 2. Sudden death sud is a major health problem all over the world. A distribution curve for the variation of the predicted logherg is shown in figure 11, which is a leftslanted gaussianshaped curve, with a peak at. Estimations are that sud is responsible for one fifth of all deaths. The effects of escitalopram and citalopram on the human etheragogorelated gene herg channels expressed in human embryonic kidney cells were investigated using voltageclamp and western blot analyses. Pdf structural determinants of herg channel block by.
Ikr, which is important for cardiac repolarization. Using immunoprecipitations, we show that the cytosolic chaperones heat shock protein hsp 70 and hsp90, but not grp94, interact with herg wild type wt during maturation. Here, we describe a peptide isolated from a cone snail that blocks voltage. In the present study, we describe a highcapacity, 384 and 1,536well plate, functional thallium flux assay for the herg channel that fulfills these criteria. Blockade of herg potassium currents by fluvoxamine. Poremodulating toxins exploit inherent slow inactivation. The most common causes of sud are cardiac, but there are also noncardiac reasons, such as neurogenic conditions, catecholamine toxicity, asthma attacks etc. In silico analysis of conformational changes induced by. The potential of antimalarial compounds derived from african. Apamin blocks sk channels k ca 2, and served as a primary pharmacological tool to distinguish between k ca 2 channels and k ca 1. Bajaj s and han j 2019 venomderived peptide modulators of cationselective channels. One key gender difference resides in the electrocardiogram. Computeraided drug design cadd often involves virtual screening vs of large compound datasets and the availability of such is vital for drug discovery protocols.
Localization of the ergtoxin1 receptors on the voltage sensing. Vandenberg ji1, perry md, perrin mj, mann sa, ke y, hill ap. How druglike are naturally occurring anticancer compounds. The effects of escitalopram and citalopram on the human etheragogorelated gene herg channels expressed in human embryonic kidney cells were investigated using voltageclamp and western blot. Using immunoprecipitations, we show that the cytosolic chaperones heat shock protein hsp 70 and hsp90, but not grp94.
Frontiers venomderived peptide modulators of cation. To explore this role, we created in silica models of the herg1 pore domain based on the kvap. These features are critical for normal cardiac repolarisation as well as in preventing lethal ventricular arrhythmias. A pharmacologically validated, highcapacity, functional. Herg channel blockade by therapeutically and structurally diverse drugs results in the acquired form of long qt syndrome. Sep 18, 20 escitalopram, a selective serotonin reuptake inhibitor, is the pharmacologically active senantiomer of the racemic mixture of rscitalopram and is widely used in the treatment of depression. Pdf an update on the structure of herg researchgate. Properties of herg channels stably expressed in hek 293. The level of channel block depends therefore not only on the drug concentration, but also on the pulse protocol kirsch et al. Comparison of kinetic properties of quinidine and dofetilide block of herg channels. The potential of antimalarial compounds derived from.
Waldegger s, niemeyer g, morike k, wagner ca, suessbrich h, busch ae, et al. In potassium channels, the open conformation relies on the spatial distribution of structural water molecules buried in protein pockets that surround the central pore. While arrhythmia, qt prolongation, and action potential parameters have been explicitly recommended as test criteria ich expert working group safety of the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use, 2005, the desire to assess and correct arrhythmogenic risk as early in the drug. Bepridil block of recombinant human cardiac iks current. This assay was optimized and validated using different structural classes of herg inhibitors. Venomderived peptide modulators of cationselective channels. Alignment of cyclic nucleotide binding domain channels revealed an evolutionary conserved sequence hwxagc in the s5 domain. An in silico evaluation of the admet profile of the.
Compliance to lipinskis rule of five and jorgensens rule of three have been used to assess oral availability, by making use of popular parameters like. Interactions of h562 in the s5 helix with t618 and s621 in. In other words the position of f627 in herg t and herg ts is anomalous in the context of other k v channels and herg ts s631a that have more limited inactivation properties, leading to the suggestion that herg t and herg ts represents an inactivated state as would be expected in the absence of a membrane potential i. In the search for compound hits for the design andor development of new drugs against the disease, many research teams have resorted to african medicinal plants in order to identify lead compounds. A detailed insight into the herg channel drug receptor sites is key to the production of pharmacophore models that may help eliminate potential herg. Modification by kcne1 variants of the herg potassium. Mutations in herg leading to partial or complete loss of function prolong the ventricular action potential and. Mutations in drug binding sites y652a or f656c of the herg channel significantly attenuated the herg current blockade by fluconazole.
Progress in understanding the molecular basis of its unusual gating kinetics european biophysics journal 2004 33 8997, european biophysics journal, vol. Threedimensional molecular models were generated for antimalarial compounds of african origin from weakly active. A novel genetic modifier for clarithromycinrelated. We reasoned that histidine 562 in herg1 could play an important structurefunction role.
Properties of herg channels stably expressed in hek 293 cells. In addition, fluconazole inhibited the trafficking of herg protein by western blot analysis and confocal microscopy, respectively. Escitalopram, a selective serotonin reuptake inhibitor, is the pharmacologically active senantiomer of the racemic mixture of rscitalopram and is widely used in the treatment of depression. In the search for compound hits for the design and or development of new drugs against the disease, many research teams have resorted to african medicinal plants in order to identify lead compounds. Ceramide modulates herg potassium channel gating by. These channels are important in cardiac action potential repolarization 18, 49, 51.
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