Small-Molecule Inhibitors of Myosin Proteins

Abstract

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...

Highly selective inhibition of myosin motors provides the basis of potential therapeutic application

“…This efficiently blocks the motor in a state that is inappropriate for force production upon interaction with actin, as ATP is not cleaved, affinity for F-actin is low, and the lever arm is not primed. Previously described myosin inhibitors, such as blebbistatin or pentabromopseudilin (3,11,12), trap the motor in the PPS state at the beginning of the force production event (Fig. S4E).…”

“…Several myosins have also been linked to genetic disorders where either gain or loss of motor function can lead to disease. These motor proteins represent promising targets for the development of drugs modulating force production in cells, tissues, and muscle (2)(3)(4). Here we report a selective, smallmolecule inhibitor of smooth muscle myosin (SMM) able to induce muscle relaxation.…”

Myosin VI regulates gene pairing and transcriptional pause release in T cells

“…The myosin II inhibitor blebbistatin (BML-EI315-0005) was purchased from Enzo Life Sciences. All myosin inhibitors were used at a concentration equal to twice the IC 50 FISH. For DNA FISH, the cells were harvested, resuspended in 1× PBS, attached onto poly-L-lysine-coated coverslips (354085; BD Bioscience), fixed with 4% (vol/vol) paraformaldehyde (pH 7.2) for 10 min, washed three times with 1× PBS, and permeabilized in 0.5% Triton X-100 in PBS for 10 min at room temperature.…”

Targeting the sarcomere to correct muscle function

“…A recent study of EMD 57033 binding to myosin suggested that its binding site involved the SH3-like subdomain of the N-terminal domain, which is a different surface to that involved in omecamtiv mecarbil binding 79 . (TABLE 2) act as negative sarcomeric modulators 80 . A crystal structure of one such inhibitor, blebbistatin, showed that this compound binds to myosin within the apex of the 50-kDa cleft (FIG.…”