{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T03:07:07Z","timestamp":1792292827057,"version":"4.4.0"},"reference-count":45,"publisher":"American Chemical Society (ACS)","issue":"20","license":[{"start":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T00:00:00Z","timestamp":1589414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology , Ministry of Science and Technology","doi-asserted-by":"publisher","award":["BT\/ 01\/ COE\/ 06\/ 02\/ 10-IISc"],"award-info":[{"award-number":["BT\/ 01\/ COE\/ 06\/ 02\/ 10-IISc"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>NS3\/4A protease of hepatitis C virus (HCV) plays an important role in viral RNA replication. A 1,4-diphenylbutanedicarboxylic acid derivative, namely, phyllanthin, extracted from the leaf of a herbal plant, Phyllanthus amarus, inhibits HCV NS3\/4A protease and replication activities. However, the reduced aqueous solubility, high toxicity, and poor oral bioavailability are major impediments with phyllanthin. We herein present a design approach to generate phyllanthin congeners in order to potentiate inhibition activity against protease. The phyllanthin congeners were synthesized by chemical methods and subjected to systematic biological studies. One of the congeners, annotated as D8, is identified as a novel and potent inhibitor of the HCV-NS3\/4Aprotease activity in vitro and the viral RNA replication in cell culture. Structural analysis using the computational-based docking approach demonstrated important noncovalent interactions between D8 and the catalytic residues of the viral protease. Furthermore, D8 was found to be significantly nontoxic in cell culture. More importantly, oral administration of D8 in BALB\/c mice proved its better tolerability and bioavailability, as compared to native phyllanthin. Taken together, this study reveals a promising candidate for developing anti-HCV therapeutics to control HCV-induced liver diseases.<\/jats:p>","DOI":"10.1021\/acsomega.0c00786","type":"journal-article","created":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T11:46:47Z","timestamp":1589456807000},"page":"11553-11562","source":"Crossref","is-referenced-by-count":5,"title":["Potent HCV NS3 Protease Inhibition\nby a Water-Soluble Phyllanthin Congener"],"prefix":"10.1021","volume":"5","author":[{"given":"Uma Reddy","family":"B","sequence":"first","affiliation":[{"name":"Indian Institute of Science , , ,","place":["Bangalore, India, 560 012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Himani","family":"Tandon","sequence":"additional","affiliation":[{"name":"Indian Institute of Science , , ,","place":["Bangalore, India, 560 012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj K.","family":"Pradhan","sequence":"additional","affiliation":[{"name":"Indian Institute of Science , , ,","place":["Bangalore, India, 560 012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harikrishnan","family":"Adhikesavan","sequence":"additional","affiliation":[{"name":"Indian Institute of Science , , ,","place":["Bangalore, India, 560 012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narayanaswamy","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Indian Institute of Science , , ,","place":["Bangalore, India, 560 012"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saumitra","family":"Das","sequence":"additional","affiliation":[{"name":"Indian Institute of Science , , ,","place":["Bangalore, India, 560 012"]},{"name":"National Institute of Biomedical Genomics , ,","place":["Kalyani, India, 741 251"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5577-8053","authenticated-orcid":true,"given":"Narayanaswamy","family":"Jayaraman","sequence":"additional","affiliation":[{"name":"Indian Institute of Science , , ,","place":["Bangalore, India, 560 012"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,5,14]]},"reference":[{"key":"2026090207345714800_cit1","doi-asserted-by":"publisher","first-page":"3602","DOI":"10.1016\/j.celrep.2019.05.063","article-title":"Spatiotemporal\ncoupling of the hepatitis\nC virus replication cycle by creating a lipid droplet-proximal membranous\nreplication compartment","volume":"27","author":"Lee","year":"2019","journal-title":"Cell Rep."},{"key":"2026090207345714800_cit2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-3-642-27340-7_1","article-title":"The origin\nof hepatitis C virus","volume":"369","author":"Simmonds","year":"2013","journal-title":"Curr. Top. Microbiol.\nImmunol."},{"key":"2026090207345714800_cit3","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1002\/hep.20032","article-title":"Structural\nbiology of hepatitis C virus","volume":"39","author":"Penin","year":"2004","journal-title":"Hepatology"},{"key":"2026090207345714800_cit4","first-page":"129","article-title":"Role of nonstructural\nproteins in HCV replication","volume-title":"Hepatitis C virus","author":"Suzuki","year":"2016"},{"key":"2026090207345714800_cit5","doi-asserted-by":"publisher","first-page":"5362","DOI":"10.1128\/jvi.03188-14","article-title":"Protease inhibitors block multiple functions of the\nNS3\/4A protease-helicase during hepatitis C virus life cycle","volume":"89","author":"McGivern","year":"2015","journal-title":"J. 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Soc.,\nPerkin Trans. 1"},{"key":"2026090207345714800_cit29","doi-asserted-by":"publisher","first-page":"5051","DOI":"10.1016\/s0040-4020(01)81084-x","article-title":"Preparation of (R)-veratryl-\nand (R)-(3-methoxybenzyl)succinates","volume":"45","author":"Barnier","year":"1989","journal-title":"Tetrahedron"},{"key":"2026090207345714800_cit30","doi-asserted-by":"publisher","first-page":"4315","DOI":"10.1016\/j.tetlet.2004.04.008","article-title":"Highly diastereoselective alkylation of vicinal dianions\nof chiralsuccinic acid derivatives: a new general strategy to (R)-\u03b2-arylmethyl-\u03b3-butyrolactones","volume":"45","author":"Pohmakotr","year":"2004","journal-title":"Tetrahedron Lett."},{"key":"2026090207345714800_cit31","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/0003-2697(84)90553-0","article-title":"Fluorescein\nisothiocyanate-labeled\ncasein assay for proteolytic enzymes","volume":"143","author":"Twining","year":"1984","journal-title":"Anal.\nBiochem."},{"key":"2026090207345714800_cit32","doi-asserted-by":"publisher","first-page":"3753","DOI":"10.1128\/jvi.68.6.3753-3760.1994","article-title":"Both NS3 and\nNS4A are required for proteolytic processing of Hepatitis C virus\nnonstructural proteins","volume":"68","author":"Failla","year":"1994","journal-title":"J. Virol."},{"key":"2026090207345714800_cit33","doi-asserted-by":"publisher","first-page":"7999","DOI":"10.1128\/jvi.00348-07","article-title":"Differential\nrequirements of NS4A for internal NS3 cleavage and polyprotein processing\nof Hepatitis C virus","volume":"81","author":"Kou","year":"2007","journal-title":"J. Virol."},{"key":"2026090207345714800_cit34","doi-asserted-by":"publisher","first-page":"20483","DOI":"10.1074\/jbc.m500422200","article-title":"Molecular\ndeterminants\nof TRIF proteolysis mediated by the hepatitis C virus NS3\/4A protease","volume":"280","author":"Ferreon","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2026090207345714800_cit35","doi-asserted-by":"publisher","first-page":"17717","DOI":"10.1073\/pnas.0508531102","article-title":"Hepatitis C virus\nprotease NS3\/4A\ncleaves mitochondrial antiviral signaling protein off the mitochondria\nto evade innate immunity","volume":"102","author":"Li","year":"2005","journal-title":"Proc. Natl. Acad.\nSci. U.S.A."},{"key":"2026090207345714800_cit36","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/s0166-0934(02)00255-0","article-title":"A novel high throughput\nscreening assay for HCV NS3 serine protease inhibitors","volume":"107","author":"Berdichevsky","year":"2003","journal-title":"J. Virol. Methods"},{"key":"2026090207345714800_cit37","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1099\/vir.0.18997-0","article-title":"Hepatitis\nC virus RNA replication is resistant to tumour necrosis factor-\u03b1","volume":"84","author":"Frese","year":"2003","journal-title":"J. Gen. 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Commun."},{"key":"2026090207345714800_cit45","article-title":"Test No. 423:\nAcute Oral toxicity\u2013Acute Toxic Class Method","volume-title":"OECD Guidelines for the Testing of Chemicals","author":"Organization for Economic Cooperation and Development.","year":"2001"},{"key":"2026090207345714800_cit46","unstructured":"Organization for Economic Cooperation and Development.\n          .  OECD Report of the\nValidation of the Updated Test Guideline 407: Repeat Dose 28 day Oral\nToxicity Study in Laboratory Rats. Series on Testing and Assessment\nNo 59, ENV\/JM\/MONO, 2006; p 26."}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.0c00786","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/5\/20\/11553\/67711005\/acsomega.0c00786.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/5\/20\/11553\/67711005\/acsomega.0c00786.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:35:03Z","timestamp":1788348903000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/5\/20\/11553\/605771\/Potent-HCV-NS3-Protease-Inhibition-by-a-Water"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,14]]},"references-count":45,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2020,5,14]]},"published-print":{"date-parts":[[2020,5,26]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.0c00786","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,14]]}}}