Design, Synthesis, and Biological Evaluation of PKD Inhibitors

George, Kara M.; Frantz, Marie‐Céline; Bravo‐Altamirano, Karla; LaValle, Courtney R.; Tandon, Manuj; Leimgruber, Stephanie; Sharlow, Elizabeth R.; Lazo, John S.; Wang, Qiming J.; Wipf, Peter

doi:10.3390/pharmaceutics3020186

Cited by 56 publications

(38 citation statements)

References 72 publications

(86 reference statements)

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“…The recent development of selective benzoxoloazepinolone PKD inhibitor (Fig. 5 and 7) should accelerate research in this area (22,(35)(36)(37). The compound is a potent and cell-permeable inhibitor of PKD.…”

Section: Discussionmentioning

confidence: 99%

Sustained Protein Kinase D Activation Mediates Respiratory Syncytial Virus-Induced Airway Barrier Disruption

Rezaee

DeSando

Ivanov

et al. 2013

J Virol

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Understanding the regulation of airway epithelial barrier function is a new frontier in asthma and respiratory viral infections. Despite recent progress, little is known about how respiratory syncytial virus (RSV) acts at mucosal sites, and very little is known about its ability to influence airway epithelial barrier function. Here, we studied the effect of RSV infection on the airway epithelial barrier using model epithelia. 16HBE14o-bronchial epithelial cells were grown on Transwell inserts and infected with RSV strain A2. We analyzed (i) epithelial apical junction complex (AJC) function, measuring transepithelial electrical resistance (TEER) and permeability to fluorescein isothiocyanate (FITC)-conjugated dextran, and (ii) AJC structure using immunofluorescent staining. Cells were pretreated or not with protein kinase D (PKD) inhibitors. UV-irradiated RSV served as a negative control. RSV infection led to a significant reduction in TEER and increase in permeability. Additionally it caused disruption of the AJC and remodeling of the apical actin cytoskeleton. Pretreatment with two structurally unrelated PKD inhibitors markedly attenuated RSV-induced effects. RSV induced phosphorylation of the actin binding protein cortactin in a PKD-dependent manner. UV-inactivated RSV had no effect on AJC function or structure. Our results suggest that RSV-induced airway epithelial barrier disruption involves PKD-dependent actin cytoskeletal remodeling, possibly dependent on cortactin activation. Defining the mechanisms by which RSV disrupts epithelial structure and function should enhance our understanding of the association between respiratory viral infections, airway inflammation, and allergen sensitization. Impaired barrier function may open a potential new therapeutic target for RSV-mediated lung diseases. R espiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children (1) and an important cause of death in childhood (2). RSV has been identified as a source of morbidity and mortality in elderly and high-risk adults (3). RSV infects airway epithelial cells and is thought to cause tissue pathology by inducing the expression of proinflammatory mediators, leading to airway inflammation and, ultimately, an antiviral immune response (4). RSV also induces the expression of antiapoptotic genes and promotes epithelial cell survival, which is probably a strategy to ensure viral replication in infected cells (5).Emerging evidence points to a role for airway barrier dysfunction during respiratory viral infections (6), as well as in stable asthmatics (7). The airway barrier is made up of the surface mucus layer, as well as apical junction complexes (AJC) that regulate paracellular permeability (8). Previously we demonstrated that polyinosinic-polycytidylic acid [poly(I-C)], a synthetic doublestranded RNA and viral mimetic, induces potent breakdown of the airway epithelial AJC in a protein kinase D (PKD)-dependent manner (9). PKD, formerly known as PKC, is a serine/threonine protein kinase fami...

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Section: Discussionmentioning

confidence: 99%

Sustained Protein Kinase D Activation Mediates Respiratory Syncytial Virus-Induced Airway Barrier Disruption

Rezaee

DeSando

Ivanov

et al. 2013

J Virol

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“…8). [23][24][25] Several lead structures, The pH was measured electrochemically after excess compound had been filtered from the solution.…”

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confidence: 99%

A Bifunctional Dimethylsulfoxide Substitute Enhances the Aqueous Solubility of Small Organic Molecules

Sprachman

Wipf

2012

ASSAY and Drug Development Technologies

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An oxetane-substituted sulfoxide has demonstrated potential as a dimethylsulfoxide substitute for enhancing the dissolution of organic compounds with poor aqueous solubilities. This sulfoxide may find utility in applications of library storage and biological assays. For the model compounds studied, significant solubility enhancements were observed using the sulfoxide as a cosolvent in aqueous media. Brine shrimp, breast cancer (MDA-MB-231), and liver cell line (HepG2) toxicity data for the new additive are also presented, in addition to comparative IC 50 values for a series of PKD1 inhibitors.

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“…Compared with DAG, the effect of PKD can be addressed more specifically using selective inhibitors. The PKD inhibitors used here have been shown to inhibit PKD selectively, with little effect on PKC (9,33).…”

Section: Discussionmentioning

confidence: 96%

“…No statistical difference in cell capacitance was found between groups in this or any other figure. for the same period of time. To inhibit protein kinase D (PKD), we added either CID-755673 or CID-2011756 (Tocris, Bristol, UK; 40 M) to the cultures for 6 h (9,33,34,48), and control cells received DMSO (0.05%). The effect of PMA (Sigma-Aldrich; 50 nM) was also tested by adding the drug to the cultures for 6 h, and control cells received DMSO vehicle (0.05%).…”

Section: Methodsmentioning

confidence: 99%

Regulation of membrane KCNQ1/KCNE1 channel density by sphingomyelin synthase 1

Takemoto

Taniguchi

et al. 2016

American Journal of Physiology-Cell Physiology

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Sphingomyelin synthase (SMS) catalyzes the conversion of phosphatidylcholine and ceramide to sphingomyelin and diacylglycerol. We previously showed that SMS1 deficiency leads to a reduction in expression of the K ϩ channel KCNQ1 in the inner ear (Lu MH, Takemoto M, Watanabe K, Luo H, Nishimura M, Yano M, Tomimoto H, Okazaki T, Oike Y, and Song WJ. J Physiol 590: 4029 -4044, 2012), causing hearing loss. However, it remains unknown whether this change in expression is attributable to a cellular process or a systemic effect in the knockout animal. Here, we examined whether manipulation of SMS1 activity affects KCNQ1/KCNE1 currents in individual cells. To this end, we expressed the KCNQ1/KCNE1 channel in human embryonic kidney 293T cells and evaluated the effect of SMS1 manipulations on the channel using whole cell recording. Application of tricyclodecan-9-ylxanthogenate, a nonspecific inhibitor of SMSs, significantly reduced current density and altered channel voltage dependence. Knockdown of SMS1 by a short hairpin RNA, however, reduced current density alone. Consistent with this, overexpression of SMS1 increased the current density without changing channel properties. Furthermore, application of protein kinase D inhibitors also suppressed current density without changing channel properties; this effect was nonadditive with that of SMS1 short hairpin RNA. These results suggest that SMS1 positively regulates KCNQ1/KCNE1 channel density in a protein kinase D-dependent manner.KCNQ1; KCNE1; sphingomyelin synthase; PKD THE SLOWLY ACTIVATING, DELAYED rectifier potassium channel encoded by KCNQ1 (␣-subunit, also known as Kv7.1) and KCNE1 (␤-subunit, also known as Isk or minK) plays important roles in a number of organs, including the inner ear, heart, pancreas, and brain (reviewed in Refs. 1,15,19). In the heart, the KCNQ1/KCNE1 channel [also known as the cardiac slowly activating K ϩ current (I Ks ) channel] is necessary for the termination of action potentials (5,30,42), and loss of function of the I Ks channel causes prolongation of the QT interval in the ECG (26). In the inner ear, KCNQ1/KCNE1 channels are expressed exclusively on the apical surface of marginal cells of the stria vascularis (14, 29), maintaining the endocochlear potential and thereby the high sensitivity of the inner ear to sound. Dysfunction of KCNQ1/KCNE1 channels in the inner ear causes hearing impairment or congenital deafness (3,15,27). Understanding how KCNQ1/KCNE1 channels are regulated is, therefore, of profound biological significance.We previously showed that KCNQ1 expression in the inner ear may be subject to regulation by sphingomyelin synthase 1 (SMS1) (21). SMS1 is one of the two isoforms of the enzyme that catalyzes the conversion of phosphatidylcholine and ceramide to sphingomyelin and diacylglycerol (DAG) (reviewed in Refs. 18, 38). We showed that SMS1 deficiency results in hearing impairment, which is attributable to a reduction in endocochlear potential caused by aberrant KCNQ1 protein expression in the marginal cells of the stria ...

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Design, Synthesis, and Biological Evaluation of PKD Inhibitors

Cited by 56 publications

References 72 publications

Sustained Protein Kinase D Activation Mediates Respiratory Syncytial Virus-Induced Airway Barrier Disruption

Sustained Protein Kinase D Activation Mediates Respiratory Syncytial Virus-Induced Airway Barrier Disruption

A Bifunctional Dimethylsulfoxide Substitute Enhances the Aqueous Solubility of Small Organic Molecules

Regulation of membrane KCNQ1/KCNE1 channel density by sphingomyelin synthase 1

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