title: An arsenical-maleimide for the generation of new targeted biochemical reagents.
abstract: The finding that arsenic trioxide is an effective treatment for acute promyelocytic leukemia has renewed interest in the pharmacological uses of inorganic and organic arsenicals. Here we synthesized and characterized the reactivity of an arsenical-maleimide (As-Mal) that can be efficiently conjugated to exposed cysteine residues in peptides and proteins with the ultimate goal of directing these As(III) species to vicinal thiols in susceptible targets within cells and tissues. As-Mal conjugated to a surface cysteine in thioredoxin provides a more potent inhibitor for Escherichia coli thioredoxin reductase than comparable simple inorganic or organic arsenicals. As-Mal can be coupled to all of the eight cysteine residues of reduced unfolded ribonuclease A or to site-specific locations using appropriate cysteine mutations. We observed particularly strong binding to the two CxxC motifs of protein disulfide isomerase using a mutant RNase in which As-Mal was specifically incorporated at residues 26 and 110. As-Mal will serve as a facile reagent for the incorporation of As(III) species into a wide range of thiol-containing proteins, biomaterials, and surfaces.
authors: Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
authors: Aparna
authors: A
authors: Sapra
authors: Colin
authors: C
authors: Thorpe
mesh_terms: D001152:Arsenicals / Q000138:chemical synthesis* / Q000737:chemistry; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D017510:Protein Folding; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors
chemical_list: D001152:Arsenicals; D008301:Maleimides; C043592:maleimide; D013880:Thioredoxin-Disulfide Reductase
references: Eur J Biochem. 2000 Oct;267(20):6110-7
references: 11012662
references: Curr Opin Chem Biol. 2012 Apr;16(1-2):92-8
references: 22342767
references: Methods Enzymol. 1995;251:8-28
references: 7651233
references: Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16348-53
references: 22988091
references: Proc Natl Acad Sci U S A. 2011 Jun 28;108(26):10650-5
references: 21670307
references: J Virol. 2007 Mar;81(5):2328-39
references: 17151113
references: Biochemistry. 2009 Jan 20;48(2):424-32
references: 19102631
references: J Clin Invest. 2012 Jun;122(6):2104-13
references: 22565308
references: Nat Biotechnol. 2012 Jan 22;30(2):184-9
references: 22267010
references: ACS Chem Biol. 2011 Mar 18;6(3):245-51
references: 21121641
references: Science. 2000 Aug 18;289(5482):1190-4
references: 10947986
references: Bioconjug Chem. 2011 Oct 19;22(10):1946-53
references: 21863904
references: Br J Haematol. 2010 Feb;148(4):627-37
references: 19995400
references: Nat Biotechnol. 2008 Aug;26(8):925-32
references: 18641636
references: J Med Chem. 2009 Oct 22;52(20):6209-16
references: 19788237
references: Antioxid Redox Signal. 2006 Mar-Apr;8(3-4):312-24
references: 16677077
references: Cancer Res. 2006 Oct 15;66(20):9895-902
references: 17047051
references: Bioorg Med Chem Lett. 2012 Jul 1;22(13):4249-53
references: 22664129
references: Trends Mol Med. 2012 Jul;18(7):385-93
references: 22682515
references: Anal Biochem. 2009 Nov 15;394(2):147-58
references: 19664585
references: Cancer Treat Rev. 2007 Oct;33(6):542-64
references: 17624680
references: J Thromb Haemost. 2011 Nov;9(11):2278-90
references: 21929690
references: Toxicol Appl Pharmacol. 1996 Sep;140(1):1-12
references: 8806864
references: Annu Rev Biochem. 1983;52:711-60
references: 6137189
references: Vitam Horm. 2012;88:333-54
references: 22391311
references: Methods Enzymol. 2012;502:123-38
references: 22208984
references: Biochim Biophys Acta. 2008 Apr;1783(4):535-48
references: 18093543
references: J Biol Chem. 1979 Oct 10;254(19):9627-32
references: 385588
references: Blood Rev. 2010 Jul-Sep;24(4-5):191-9
references: 20471733
references: Inorg Chem. 2005 Apr 18;44(8):2964-72
references: 15819584
references: Br J Haematol. 2008 Jan;140(2):223-9
references: 18028487
references: Nature. 2007 May 24;447(7143):482-6
references: 17495932
references: Adv Drug Deliv Rev. 2003 Feb 10;55(2):199-215
references: 12564977
references: Antioxid Redox Signal. 2009 Nov;11(11):2807-50
references: 19476414