{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T20:53:35Z","timestamp":1760043215545},"reference-count":0,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[1992,8]]},"abstract":"\n BACKGROUND<\/jats:title>\n Early intervention with thrombolytic agents has been shown unequivocally to reduce mortality after acute myocardial infarction. Presently used agents have disadvantages such as short half-life, immunogenicity, hypotension, and bleeding complications. Therefore, there is a need to develop improved thrombolytic drugs with novel mechanisms of action leading to improved properties.<\/jats:p>\n <\/jats:sec>\n \n METHODS AND RESULTS<\/jats:title>\n Hybrid plasminogen\/tissue-type plasminogen activator (t-PA) complementary DNA was constructed and expressed in Chinese hamster ovary cells. The chimeric protein, comprising the fibrin-binding domains of plasminogen covalently linked to the catalytic domain of t-PA, was purified and evaluated in vitro and in vivo. The hybrid was inhibited rapidly in human and animal plasmas. The mediator of this rapid inhibition was shown to be alpha 2-antiplasmin. The active center of the hybrid could be protected by reversible active center acylation with a novel inverse acylating agent, 4'-amidinophenyl-4-chloroanthranilic acid (AP-CLAN). An acylated (CLAN-) hybrid was cleared from the bloodstream of guinea pigs at 0.35 +\/- 0.02 ml\/min.kg-1 compared with a clearance rate of 36 +\/- 4 ml\/min.kg-1 for t-PA. The CLAN-plasminogen\/t-PA hybrid was evaluated in a quantitative, \"humanized\" guinea pig pulmonary embolism model and shown to be approximately threefold more potent when given by bolus than an infusion of t-PA. Furthermore, the acylated hybrid was more fibrin selective than t-PA as determined by the relation between clot lysis and fibrinogen degradation.<\/jats:p>\n <\/jats:sec>\n \n CONCLUSIONS<\/jats:title>\n An acylated, recombinant plasminogen\/t-PA hybrid has sufficiently slow clearance to be administered by bolus and is more potent and fibrin selective than t-PA in vivo.<\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/01.cir.86.2.548","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:01:09Z","timestamp":1339459269000},"page":"548-552","update-policy":"http:\/\/dx.doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["A recombinant, chimeric enzyme with a novel mechanism of action leading to greater potency and selectivity than tissue-type plasminogen activator."],"prefix":"10.1161","volume":"86","author":[{"given":"J H","family":"Robinson","sequence":"first","affiliation":[{"name":"Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M J","family":"Browne","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J E","family":"Carey","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P D","family":"Chamberlain","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C G","family":"Chapman","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D W","family":"Cronk","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I","family":"Dodd","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Entwisle","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A F","family":"Esmail","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S B","family":"Kalindjian","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, SmithKline Beecham Pharmaceuticals, Surrey, England, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/pdf\/10.1161\/01.CIR.86.2.548","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T15:46:37Z","timestamp":1715528797000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/01.CIR.86.2.548"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1992,8]]},"references-count":0,"journal-issue":{"issue":"2","published-print":{"date-parts":[[1992,8]]}},"alternative-id":["10.1161\/01.CIR.86.2.548"],"URL":"https:\/\/doi.org\/10.1161\/01.cir.86.2.548","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[1992,8]]},"assertion":[{"value":"1992-08-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}