{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:05:00Z","timestamp":1781103900345,"version":"3.54.1"},"reference-count":65,"publisher":"National Academy of Sciences","issue":"10","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,5,8]]},"abstract":"<jats:p>\n                    Transthyretin (TTR) tetramer dissociation and misfolding facilitate\n assembly into amyloid fibrils that putatively cause senile systemic\n amyloidosis and familial amyloid polyneuropathy. We have previously\n discovered more than 50 small molecules that bind to and stabilize\n tetrameric TTR, inhibiting amyloid fibril formation\n                    <jats:italic>in\n vitro<\/jats:italic>\n                    . A method is presented here to evaluate the binding\n selectivity of these inhibitors to TTR in human plasma, a complex\n biological fluid composed of more than 60 proteins and numerous small\n molecules. Our immunoprecipitation approach isolates TTR and bound\n small molecules from a biological fluid such as plasma, and quantifies\n the amount of small molecules bound to the protein by HPLC analysis.\n This approach demonstrates that only a small subset of the inhibitors\n that saturate the TTR binding sites\n                    <jats:italic>in vitro<\/jats:italic>\n                    do so in\n plasma. These selective inhibitors can now be tested in animal models\n of TTR amyloid disease to probe the validity of the amyloid hypothesis.\n This method could be easily extended to evaluate small molecule binding\n selectivity to any protein in a given biological fluid without the\n necessity of determining or guessing which other protein components may\n be competitors. This is a central issue to understanding the\n distribution, metabolism, activity, and toxicity of potential drugs.\n                  <\/jats:p>","DOI":"10.1073\/pnas.091431798","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:44:19Z","timestamp":1027680259000},"page":"5566-5571","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":100,"title":["Evaluating the binding selectivity of transthyretin amyloid fibril inhibitors in blood plasma"],"prefix":"10.1073","volume":"98","author":[{"given":"Hans E.","family":"Purkey","sequence":"first","affiliation":[{"name":"Department of Chemistry and The Skaggs Institute of Chemical\r Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,\r MB12, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael I.","family":"Dorrell","sequence":"additional","affiliation":[{"name":"Department of Chemistry and The Skaggs Institute of Chemical\r Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,\r MB12, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery W.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Chemistry and The Skaggs Institute of Chemical\r Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,\r MB12, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,5,8]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"631","volume-title":"Immunological Diseases","author":"Pepys M B","year":"1988","unstructured":"M B Pepys Immunological Diseases, ed M Samter (Little Brown, Boston) 1, 631\u2013674 (1988)."},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.61.070192.004503"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.1994.tb00001.x"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.3109\/10408369409084679"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01887400"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-5521(97)90255-6"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.3.930"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-440X(98)80016-X"},{"key":"e_1_3_3_9_2","first-page":"1","volume":"48","author":"Cohen A S","year":"1983","unstructured":"A S Cohen, T Shirahama, J D Sipe, M Skinner Lab Invest 48, 1\u20134 (1983).","journal-title":"Lab Invest"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.2.503"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1997.1348"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.4.815"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2000.3908"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00151a036"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.12.5446"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00041a032"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi952501g"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-440X(96)80089-3"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/385787a0"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-2126(97)00215-3"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(74)90291-5"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00673a014"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(78)90368-6"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)40795-3"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(88)90188-X"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.7.2843"},{"key":"e_1_3_3_27_2","first-page":"590","volume":"102","author":"Saraiva M J M","year":"1983","unstructured":"M J M Saraiva, P P Costa, D S Goodman J Lab Clin Med 102, 590\u2013603 (1983).","journal-title":"J Lab Clin Med"},{"key":"e_1_3_3_28_2","first-page":"189","volume":"48","author":"Saraiva M J M","year":"1988","unstructured":"M J M Saraiva, P P Costa, D S Goodman Adv Neurol 48, 189\u2013200 (1988).","journal-title":"Adv Neurol"},{"key":"e_1_3_3_29_2","first-page":"2439","volume-title":"The Metabolic Basis of Inherited Disease","author":"Benson M D","year":"1989","unstructured":"M D Benson, M R Wallace The Metabolic Basis of Inherited Disease, eds C R Scriver, A L Beaudet, W S Sly, D Valle (McGraw Hill, 6th Ed., New York) 2, 2439\u20132460 (1989).","edition":"6"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4684-5958-6_2"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.1380050302"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320600606"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1097\/00019052-199610000-00007"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199702133360703"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.3109\/13506120009146826"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.26.15051"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.23.13407"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0896(98)00130-8"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0896(99)00066-8"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(98)00696-9"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja993309v"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/74082"},{"key":"e_1_3_3_43_2","volume-title":"CNBr-activated Sepharose 4B Instructions","year":"1998","unstructured":"CNBr-activated Sepharose 4B Instructions (Amersham Pharmacia Biotech, Uppsala, Sweden, 1998)."},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1949.tb27297.x"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.19.6654"},{"key":"e_1_3_3_46_2","first-page":"477","volume":"34","author":"Robbins J","year":"1978","unstructured":"J Robbins, S-Y Cheng, M C Gershengorn, D Glinoer, H J Cahnmann, H Edelhoch Rec Prog Horm Res 34, 477\u2013519 (1978).","journal-title":"Rec Prog Horm Res"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1998.9097"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.1998.00345.x"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1021\/ac980531u"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-68-6-1141"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600650340"},{"key":"e_1_3_3_52_2","volume-title":"Physicians' Desk Reference","author":"Sifton D W","year":"2000","unstructured":", ed D W Sifton (Medical Economics, 54th Ed., Montvale, NJ Physicians' Desk Reference, 2000).","edition":"54"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm00307a025"},{"key":"e_1_3_3_54_2","first-page":"621","volume":"33","author":"Kaltenbronn J S","year":"1983","unstructured":"J S Kaltenbronn, R A Scherrer, F W Short, E M Jones, H R Beatty, M M Saka, C V Winder, J Wax, W R N Williamson Arzneim-Forsch 33, 621\u2013627 (1983).","journal-title":"Arzneim-Forsch"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(95)00425-4"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(83)90264-8"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinchem\/33.2.273"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1211\/0022357991772079"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(91)90517-F"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.37.1401"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1002\/jps.2600820629"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-4347(97)00178-3"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm991174y"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199426010-00004"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.3109\/13506129609045521"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.091431798","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T19:13:14Z","timestamp":1649790794000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.091431798"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,5,8]]},"references-count":65,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2001,5,8]]}},"alternative-id":["10.1073\/pnas.091431798"],"URL":"https:\/\/doi.org\/10.1073\/pnas.091431798","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,5,8]]},"assertion":[{"value":"2000-09-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2001-05-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}