{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T23:16:14Z","timestamp":1788477374012,"version":"build-2803163510"},"reference-count":42,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2019,7,2]],"date-time":"2019-07-02T00:00:00Z","timestamp":1562025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["K01DK102772"],"award-info":[{"award-number":["K01DK102772"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology , Ministry of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,7,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations of cardiac calsequestrin (CASQ2) that impair its characteristic ability of Ca2+-induced polymerization\u2013depolymerization. However, stabilizing the CASQ2 polymer by pharmacological agents to treat CPVT has not been reported so far. Here, we tested whether small molecules can stabilize CASQ2 polymers. We synthesized 24 glycinate\/alaninate\/acetate \u03b1-pyranone analogs and conducted the CASQ2 depolymerization assay. Most of the molecules of this class of compounds inhibited the depolymerization of the protein upon Ca2+ chelation by ethylene glycol tetraacetic acid. Structure\u2013activity relationship studies revealed that the compounds with the 4-fluoro-phenyl group at the C-6 position of the pyranone ring and open-chain primary amine at C-4 are the most active of the class. This is the first report of an \u03b1-pyranone class of compounds with the ability to stabilize CASQ2 polymers and opens up the possibility to target Ca2+-release disorders via modulation of CASQ2 polymerization.<\/jats:p>","DOI":"10.1021\/acsomega.9b01113","type":"journal-article","created":{"date-parts":[[2019,7,2]],"date-time":"2019-07-02T15:03:18Z","timestamp":1562079798000},"page":"11508-11514","source":"Crossref","is-referenced-by-count":3,"title":["First Insight on Small Molecules as Cardiac Calsequestrin Stabilizers"],"prefix":"10.1021","volume":"4","author":[{"given":"Harapriya","family":"Chakravarty","sequence":"first","affiliation":[{"name":"Birla Institute of Technology, Mesra , , ,","place":["Ranchi, India, 835215"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandralata","family":"Bal","sequence":"additional","affiliation":[{"name":"Birla Institute of Technology, Mesra , , ,","place":["Ranchi, India, 835215"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3772-2317","authenticated-orcid":true,"given":"Monika","family":"Yadav","sequence":"additional","affiliation":[{"name":"Birla Institute of Technology, Mesra , , ,","place":["Ranchi, India, 835215"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nivedita","family":"Jena","sequence":"additional","affiliation":[{"name":"KIIT University , ,","place":["Bhubaneswar, India, 751021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naresh C.","family":"Bal","sequence":"additional","affiliation":[{"name":"KIIT University , ,","place":["Bhubaneswar, India, 751021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5738-1607","authenticated-orcid":true,"given":"Ashoke","family":"Sharon","sequence":"additional","affiliation":[{"name":"Birla Institute of Technology, Mesra , , ,","place":["Ranchi, India, 835215"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,7,2]]},"reference":[{"key":"2026090318105103800_cit1","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1161\/CIRCRESAHA.111.256560","article-title":"Abnormal\ntermination of Ca2+ release is a common defect of RyR2 mutations associated\nwith cardiomyopathies","volume":"110","author":"Tang","year":"2012","journal-title":"Circ. Res."},{"key":"2026090318105103800_cit2","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1172\/JCI24159","article-title":"Altered intracellular\nCa2+ handling\nin heart failure","volume":"115","author":"Yano","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2026090318105103800_cit3","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1146\/annurev.physiol.67.040403.114521","article-title":"Intracellular calcium release and\ncardiac disease","volume":"67","author":"Wehrens","year":"2005","journal-title":"Annu. Rev. Physiol."},{"key":"2026090318105103800_cit4","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1007\/s10557-016-6682-1","article-title":"Beta-blockers\nand calcium channel\nblockers: first line agents","volume":"30","author":"Pascual","year":"2016","journal-title":"Cardiovasc. Drugs\nTher."},{"key":"2026090318105103800_cit5","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1007\/s12471-014-0549-5","article-title":"New antiarrhythmic\ntargets to control intracellular calcium handling","volume":"22","author":"Driessen","year":"2014","journal-title":"Neth. Heart J."},{"key":"2026090318105103800_cit6","doi-asserted-by":"publisher","first-page":"2935","DOI":"10.1007\/s00018-012-1199-7","article-title":"Functional\ninteraction between calsequestrin and ryanodine receptor in the heart","volume":"70","author":"Gaburjakova","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"2026090318105103800_cit7","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1083\/jcb.113.4.779","article-title":"Intracellular\nCa2+ stores in chicken Purkinje neurons: differential distribution\nof the low affinity-high capacity Ca2+ binding protein, calsequestrin,\nof Ca2+ ATPase and of the ER lumenal protein, Bip","volume":"113","author":"Villa","year":"1991","journal-title":"J. Cell Biol."},{"key":"2026090318105103800_cit8","doi-asserted-by":"publisher","first-page":"6764","DOI":"10.1021\/bi00442a033","article-title":"Postulated role of\ncalsequestrin in the regulation of calcium release from sarcoplasmic\nreticulum","volume":"28","author":"Ikemoto","year":"2002","journal-title":"Biochemistry"},{"key":"2026090318105103800_cit9","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.pbiomolbio.2003.07.001","article-title":"Calsequestrin and the calcium release\nchannel of skeletal and cardiac muscle","volume":"85","author":"Beard","year":"2004","journal-title":"Prog.\nBiophys. Mol. Biol."},{"key":"2026090318105103800_cit10","doi-asserted-by":"publisher","first-page":"18026","DOI":"10.1074\/jbc.M311553200","article-title":"Comparing\nskeletal and cardiac calsequestrin\nstructures and their calcium binding","volume":"279","author":"Park","year":"2004","journal-title":"J. Biol.\nChem."},{"key":"2026090318105103800_cit11","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s00249-009-0449-6","article-title":"Ca 2+ signaling\nin striated muscle: the elusive roles\nof triadin, junctin, and calsequestrin","volume":"39","author":"Beard","year":"2009","journal-title":"Eur.\nBiophys. J."},{"key":"2026090318105103800_cit12","doi-asserted-by":"publisher","first-page":"2801","DOI":"10.1016\/S0006-3495(98)77723-9","article-title":"Regulation\nof the cardiac ryanodine receptor channel\nby luminal Ca2+ involves luminal Ca2+ sensing sites","volume":"75","author":"Gyo\u0308rke","year":"1998","journal-title":"Biophys. J."},{"key":"2026090318105103800_cit13","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1086\/324565","article-title":"A missense mutation\nin a highly conserved region of CASQ2 is associated with autosomal\nrecessive catecholamine-induced polymorphic ventricular tachycardia\nin Bedouin families from Israel","volume":"69","author":"Lahat","year":"2001","journal-title":"Am. J. Hum.\nGenet."},{"key":"2026090318105103800_cit14","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1042\/BJ20080163","article-title":"Catecholaminergic polymorphic ventricular\ntachycardia-related mutations R33Q and L167H alter calcium sensitivity\nof human cardiac calsequestrin","volume":"413","author":"Valle","year":"2008","journal-title":"Biochem. J."},{"key":"2026090318105103800_cit15","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1161\/CIRCRESAHA.108.171660","article-title":"Unexpected structural\nand functional consequences of the R33Q homozygous mutation in cardiac\ncalsequestrin","volume":"103","author":"Rizzi","year":"2008","journal-title":"Circ. Res."},{"key":"2026090318105103800_cit16","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1161\/CIRCULATIONAHA.106.623793","article-title":"Clinical phenotype and functional characterization\nof CASQ2 mutations associated with catecholaminergic polymorphic ventricular\ntachycardia","volume":"114","author":"di Barletta","year":"2006","journal-title":"Circulation"},{"key":"2026090318105103800_cit17","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1016\/j.jmb.2007.08.055","article-title":"Characterization\nof human cardiac\ncalsequestrin and its deleterious mutants","volume":"373","author":"Kim","year":"2007","journal-title":"J.\nMol. Biol."},{"key":"2026090318105103800_cit18","doi-asserted-by":"publisher","first-page":"3076","DOI":"10.1074\/jbc.M109.053892","article-title":"The calsequestrin mutation CASQ2 D307H does\nnot affect protein stability and targeting to the junctional sarcoplasmic\nreticulum but compromises its dynamic regulation of calcium buffering","volume":"285","author":"Kalyanasundaram","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026090318105103800_cit19","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.cardiores.2007.03.002","article-title":"A mutation in calsequestrin, CASQ2D307H, impairs sarcoplasmic reticulum Ca2+ handling\nand causes complex ventricular arrhythmias in mice","volume":"75","author":"Dirksen","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"2026090318105103800_cit20","doi-asserted-by":"publisher","first-page":"17188","DOI":"10.1074\/jbc.M109.096354","article-title":"The catecholaminergic\npolymorphic\nventricular tachycardia mutation R33Q disrupts the N-terminal structural\nmotif that regulates reversible calsequestrin polymerization","volume":"285","author":"Bal","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026090318105103800_cit21","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1042\/BJ20101771","article-title":"Probing cationic\nselectivity of cardiac calsequestrin and its CPVT mutants","volume":"435","author":"Bal","year":"2011","journal-title":"Biochem. J."},{"key":"2026090318105103800_cit22","doi-asserted-by":"publisher","first-page":"2510","DOI":"10.1172\/JCI29128","article-title":"Casq2 deletion\ncauses sarcoplasmic reticulum volume\nincrease, premature Ca 2+ release, and catecholaminergic polymorphic\nventricular tachycardia","volume":"116","author":"Knollmann","year":"2006","journal-title":"J. Clin. Invest."},{"issue":"20","key":"2026090318105103800_cit23","doi-asserted-by":"crossref","first-page":"11759","DOI":"10.1073\/pnas.1932318100","article-title":"Calsequestrin determines the functional size and stability\nof cardiac intracellular calcium stores: mechanism for hereditary\narrhythmia","volume":"100","author":"Terentyev","year":"2003","journal-title":"Proceedings of the National Academy\nof Sciences"},{"key":"2026090318105103800_cit24","doi-asserted-by":"publisher","first-page":"14326","DOI":"10.3390\/ijms131114326","article-title":"Molecular mechanisms\nof pharmaceutical drug binding into calsequestrin","volume":"13","author":"Subra","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"2026090318105103800_cit25","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1124\/mol.104.005728","article-title":"Investigations of calsequestrin as a target for anthracyclines:\ncomparison of functional effects of daunorubicin, daunorubicinol,\nand trifluoperazine","volume":"67","author":"Charlier","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"2026090318105103800_cit26","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.drugalcdep.2013.06.012","article-title":"Potential\nrole of cardiac calsequestrin in the lethal arrhythmic effects of\ncocaine","volume":"133","author":"Sanchez","year":"2013","journal-title":"Drug Alcohol Depend."},{"key":"2026090318105103800_cit27","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1006\/taap.2000.9065","article-title":"Sarcoplasmic\nreticulum calcium release is stimulated and inhibited by daunorubicin\nand daunorubicinol","volume":"169","author":"Olson","year":"2000","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"2026090318105103800_cit28","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.ejphar.2010.08.001","article-title":"Potential\nadverse interaction of human cardiac calsequestrin","volume":"646","author":"Kang","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"2026090318105103800_cit29","doi-asserted-by":"publisher","first-page":"47","DOI":"10.7326\/0003-4819-125-1-199607010-00008","article-title":"Anthracycline-induced\ncardiotoxicity","volume":"125","author":"Shan","year":"1996","journal-title":"Ann. Intern. Med."},{"key":"2026090318105103800_cit30","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/0022-2828(89)90782-7","article-title":"Doxorubicin-induced\ncalcium release from cardiac sarcoplasmic reticulum vesicles","volume":"21","author":"Kim","year":"1989","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2026090318105103800_cit31","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1161\/01.RES.67.5.1167","article-title":"Biphasic effects\nof doxorubicin on the calcium release channel from sarcoplasmic reticulum\nof cardiac muscle","volume":"67","author":"Ondrias","year":"1990","journal-title":"Circ. Res."},{"key":"2026090318105103800_cit32","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1016\/S0024-3205(02)01524-2","article-title":"Doxorubicin\ndirectly binds to the cardiac-type ryanodine receptor","volume":"70","author":"Saeki","year":"2002","journal-title":"Life Sci."},{"key":"2026090318105103800_cit33","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/S0026-895X(25)10840-7","article-title":"Anthraquinone-sensitized\nCa2+ release channel from rat cardiac sarcoplasmic reticulum: possible\nreceptor-mediated mechanism of doxorubicin cardiomyopathy","volume":"37","author":"Pessah","year":"1990","journal-title":"Mol. Pharmacol."},{"key":"2026090318105103800_cit34","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1124\/mol.114.093849","article-title":"Adverse effects\nof doxorubicin and its metabolic product on cardiac RyR2 and SERCA2A","volume":"86","author":"Hanna","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"2026090318105103800_cit35","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/128_2007_11","article-title":"Anthracycline\ncardiotoxicity","volume-title":"Anthracycline Chemistry\nand Biology II","author":"Menna","year":"2007"},{"key":"2026090318105103800_cit36","doi-asserted-by":"publisher","first-page":"6261","DOI":"10.1016\/j.bmcl.2012.07.098","article-title":"Structure based molecular design,\nsynthesis and biological evaluation of \u03b1-pyrone analogs as anti-HSV\nagent","volume":"22","author":"Karampuri","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"2026090318105103800_cit37","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1021\/ml400432f","article-title":"Synthesis and Anti-HCV Activity of\n4-Hydroxyamino \u03b1-Pyranone\nCarboxamide Analogues","volume":"5","author":"Konreddy","year":"2013","journal-title":"ACS Med. Chem. Lett."},{"key":"2026090318105103800_cit38","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1038\/nsb0698-476","article-title":"Crystal structure of calsequestrin from rabbit skeletal muscle sarcoplasmic\nreticulum","volume":"5","author":"Wang","year":"1998","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026090318105103800_cit39","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1093\/bioinformatics\/bti770","article-title":"The SWISS-MODEL workspace:\na web-based environment for protein structure homology modelling","volume":"22","author":"Arnold","year":"2006","journal-title":"Bioinformatics"},{"key":"2026090318105103800_cit40","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/bip.22534","article-title":"The C-terminal\ncalcium-sensitive disordered motifs\nregulate isoform-specific polymerization characteristics of calsequestrin","volume":"103","author":"Bal","year":"2015","journal-title":"Biopolymers"},{"key":"2026090318105103800_cit41","unstructured":"Maestro; Schro\u0308dinger,\nLLC: New York, NY, 2017."},{"key":"2026090318105103800_cit42","volume-title":"Release\n3.5.","author":"Visualizer","year":"2012"}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.9b01113","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/4\/7\/11508\/68311799\/acsomega.9b01113.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/4\/7\/11508\/68311799\/acsomega.9b01113.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T22:30:35Z","timestamp":1788474635000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/4\/7\/11508\/1574591\/First-Insight-on-Small-Molecules-as-Cardiac"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,2]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,7,2]]},"published-print":{"date-parts":[[2019,7,31]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.9b01113","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,2]]}}}