The small molecule tool (S)-(−)-blebbistatin: novel insights of relevance to myosin inhibitor design

Lucas-Lopez, Cristina; Allingham, John S.; Lébl, Tomáš; Lawson, Christopher P.; Brenk, Ruth; Sellers, James R.; Rayment, Ivan; Westwood, Nicholas J.

doi:10.1039/b801223g

Cited by 37 publications

(27 citation statements)

References 32 publications

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“…Myosins In some related studies, blebbistatin was chemically modified to evaluate the biological effect of its derivatives and three new protein-inhibitor structures were obtained (PDBs: 3BZ7, 3BZ8 and 3BZ9) [354]. Similarly, other inhibitors were also studied such as pentabromopseudilin (PDB code: 2JHR) [355], pentachloropseudilin (PDB: 2XEL) [356], tribromodichloropseudilin (PDB: 2XO8) [357] and pentachlorocarbazole (PDB: 2X9H).…”

Section: Myosinsmentioning

confidence: 99%

Vanadium and proteins: Uptake, transport, structure, activity and function

Pessoa

Garribba

Santos

et al. 2015

Coordination Chemistry Reviews

177

104

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Section: Myosinsmentioning

confidence: 99%

Vanadium and proteins: Uptake, transport, structure, activity and function

Pessoa

Garribba

Santos

et al. 2015

Coordination Chemistry Reviews

177

104

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“…This compound prevents the contraction of the actin/myosin cytoskeleton (Straight et al, 2003; Lucas-Lopez et al, 2008). Importantly, (-)-blebbistatin does not prevent the thrombin-induced increase in the MLC phosphorylation status, indicating that it does not affect the upstream signaling pathways controlling the activity of kinases or phosphatases that impact the MLC phosphorylation status (Ponsaerts et al, 2008).…”

Section: Bovine Corneal Endothelial Cell Monolayers As a Primary Cellmentioning

confidence: 99%

Cx43-hemichannel function and regulation in physiology and pathophysiology: insights from the bovine corneal endothelial cell system and beyond

et al. 2014

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Intercellular communication in primary bovine corneal endothelial cells (BCECs) is mainly driven by the release of extracellular ATP through Cx43 hemichannels. Studying the characteristics of Ca2+-wave propagation in BCECs, an important form of intercellular communication, in response to physiological signaling events has led to the discovery of important insights in the functional properties and regulation of native Cx43 hemichannels. Together with ectopic expression models for Cx43 hemichannels and truncated/mutated Cx43 versions, it became very clear that loop/tail interactions play a key role in controlling the activity of Cx43 hemichannels. Interestingly, the negative regulation of Cx43 hemichannels by enhanced actin/myosin contractility seems to impinge upon loss of these loop/tail interactions essential for opening Cx43 hemichannels. Finally, these molecular insights have spurred the development of novel peptide tools that can selectively inhibit Cx43 hemichannels, but neither Cx43 gap junctions nor hemichannels formed by other Cx isoforms. These tools now set the stage to hunt for novel physiological functions for Cx43 hemichannels in primary cells and tissues and to tackle disease conditions associated with excessive, pathological Cx43-hemichannel openings.

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“…On a more specific level, the presently characterized myosin inhibitors themselves can serve as templates for future drug development. Indeed, the chemical preparation of blebbistatin analogs via modification of its tricyclic core has already been evaluated as a method of developing myosin inhibitors with increased binding affinities and different selectivity [84,85]. This methodology was applied successfully in a recent study synthesizing an aryl azido derivative of blebbistatin that can be covalently cross-linked to myosin II, thereby reducing the concentration necessary for in vivo studies and reducing concerns due to the low in vivo binding affinity of blebbistatin [34].…”

Section: Future Perspectivementioning

confidence: 99%

Small-Molecule Inhibitors of Myosin Proteins

et al. 2012

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Advances in screening and computational methods have enhanced recent efforts to discover/ design small-molecule protein inhibitors. One attractive target for inhibition is the myosin family of motor proteins. Myosins function in a wide variety of cellular processes, from intracellular trafficking to cell motility, and are implicated in several human diseases (e.g., cancer, hypertrophic cardiomyopathy, deafness and many neurological disorders). Potent and selective myosin inhibitors are, therefore, not only a tool for understanding myosin function, but are also a resource for developing treatments for diseases involving myosin dysfunction or overactivity. This review will provide a brief overview of the characteristics and scientific/therapeutic applications of the presently identified small-molecule myosin inhibitors before discussing the future of myosin inhibitor and activator design.The identification and characterization of pharmacological compounds that inhibit the functional activity of one or more specific proteins or processes has been the subject of much scientific investigation. On a basic science level, these membrane-permeable compounds provide the scientific community with a tool for the targeted and functional inhibition of a given protein in the cell; a potent means of evaluating the intracellular functions of that protein [1,2]. From a biomedical standpoint, the characterization of these small-molecule inhibitors affords an opportunity for the development of novel disease treatments centering on the repression of an offensive molecule or the reversal of its downstream effects [3][4][5].At present, several complementary methods for obtaining suitable small-molecule inhibitors of specific proteins exist. Traditional methods in inhibitor discovery involve the systematic testing of a series of chemically synthesized or naturally occurring compounds. Advances in robotics and data processing have made it possible to use high-throughput screens to test libraries of thousands or even millions of potential drugs for their ability to inhibit the function of a specific protein in a targeted biochemical or cellular assay [6][7][8]. These inhibitor discovery processes are complemented by more precise methods in small-molecule inhibitor design. Structure-based methods rely on the use of x-ray crystallographic or NMRbased structures of a protein of interest to design small molecules likely to bind and inhibit protein function [9,10]. Computer-aided inhibitor design uses computational methods to optimize potential inhibitors identified by screening or structure-based methods, to virtually © 2013 Folma Buss * Author for correspondence: Tel.: +44 1223 763348, Fax: +44 1223 762640, fb207@cam.ac.uk. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance w...

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The small molecule tool (S)-(−)-blebbistatin: novel insights of relevance to myosin inhibitor design

Cited by 37 publications

References 32 publications

Vanadium and proteins: Uptake, transport, structure, activity and function

Vanadium and proteins: Uptake, transport, structure, activity and function

Cx43-hemichannel function and regulation in physiology and pathophysiology: insights from the bovine corneal endothelial cell system and beyond

Small-Molecule Inhibitors of Myosin Proteins

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