{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T02:01:30Z","timestamp":1782266490416,"version":"3.54.5"},"reference-count":82,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2015,5,10]],"date-time":"2015-05-10T00:00:00Z","timestamp":1431216000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KO1390\/10-1"],"award-info":[{"award-number":["KO1390\/10-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Peptide Science"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:p>Cystine\u2010knot peptides sharing a common fold but displaying a notably large diversity within the primary structure of flanking loops have shown great potential as scaffolds for the development of therapeutic and diagnostic agents. In this study, we demonstrated that the cystine\u2010knot peptide MCoTI\u2010II, a trypsin inhibitor from <jats:italic>Momordica cochinchinensis<\/jats:italic>, can be engineered to bind to cytotoxic T lymphocyte\u2010associated antigen 4 (CTLA\u20104), an inhibitory receptor expressed by T lymphocytes, that has emerged as a target for the treatment of metastatic melanoma. Directed evolution was used to convert a cystine\u2010knot trypsin inhibitor into a CTLA\u20104 binder by screening a library of variants using yeast surface display. A set of cystine\u2010knot peptides possessing dissociation constants in the micromolar range was obtained; the most potent variant was synthesized chemically. Successive conjugation with neutravidin, fusion to antibody Fc domain or the oligomerization domain of C4b binding protein resulted in oligovalent variants that possessed enhanced (up to 400\u2010fold) dissociation constants in the nanomolar range. Our data indicate that display of multiple knottin peptides on an oligomeric scaffold protein is a valid strategy to improve their functional affinity with ramifications for applications in diagnostics and therapy. Copyright \u00a9 2015 European Peptide Society and John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/psc.2782","type":"journal-article","created":{"date-parts":[[2015,5,11]],"date-time":"2015-05-11T03:01:09Z","timestamp":1431313269000},"page":"651-660","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Cystine\u2010knot peptides targeting cancer\u2010relevant human cytotoxic T lymphocyte\u2010associated antigen 4 (CTLA\u20104)"],"prefix":"10.1002","volume":"21","author":[{"given":"Franziska","family":"Maa\u00df","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry Technische Universit\u00e4t Darmstadt  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joycelyn","family":"W\u00fcstehube\u2010Lausch","sequence":"additional","affiliation":[{"name":"BioNTech AG  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Dickgie\u00dfer","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry Technische Universit\u00e4t Darmstadt  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Valldorf","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry Technische Universit\u00e4t Darmstadt  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Reinwarth","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry Technische Universit\u00e4t Darmstadt  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans\u2010Ulrich","family":"Schmoldt","sequence":"additional","affiliation":[{"name":"BioNTech AG  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matin","family":"Daneschdar","sequence":"additional","affiliation":[{"name":"BioNTech AG  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Avrutina","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry Technische Universit\u00e4t Darmstadt  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ugur","family":"Sahin","sequence":"additional","affiliation":[{"name":"BioNTech AG  Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Kolmar","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry Technische Universit\u00e4t Darmstadt  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,5,10]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2009.05.004"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-0101(00)00160-4"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2008.06440.x"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6807-8-54"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules171112533"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000499"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016112"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2006.09.028"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/10611860600648254"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.2174\/138161211798999465"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-396962-0.00009-4"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/bip.22284"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0076956"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb4000585"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2495"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno\/v01p0403"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1311333110"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060498"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101666200"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja405108p"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.5414\/CPP44478"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2014.06.047"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00017"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201200984"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.4155\/tde.12.99"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.8.6.565"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200500062"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/ac500926f"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc900217h"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.4161\/mabs.21024"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2006.05567.x"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/423829"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-0813"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.2.459"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1323143"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1496399"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.271.5256.1734"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1533209100"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1515"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar1688"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200324021"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3463"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi0106639"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi9929756"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.2144\/000112953"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0697-553"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzq002"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-557-2_20"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1021\/bc300184m"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2012.12.017"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201200604"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2010.10.012"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.11.004"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2014.03.011"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb200039s"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201203857"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm301468k"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200900534"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-06-359141"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.10.028"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920310790274617"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biotechadv.2013.08.021"},{"key":"e_1_2_5_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biotechadv.2007.02.003"},{"key":"e_1_2_5_66_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.2.996"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0161-5890(01)00023-2"},{"key":"e_1_2_5_68_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/9.2.203"},{"key":"e_1_2_5_69_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001678"},{"key":"e_1_2_5_70_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-62703-673-3_7"},{"key":"e_1_2_5_71_1","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzi049"},{"key":"e_1_2_5_72_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-139-0_4"},{"key":"e_1_2_5_73_1","doi-asserted-by":"publisher","DOI":"10.2165\/00063030-200822010-00002"},{"key":"e_1_2_5_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-1759(01)00563-4"},{"key":"e_1_2_5_75_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200900023"},{"key":"e_1_2_5_76_1","doi-asserted-by":"publisher","DOI":"10.1021\/nn201397z"},{"key":"e_1_2_5_77_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201003432"},{"key":"e_1_2_5_78_1","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1958.0046"},{"key":"e_1_2_5_79_1","first-page":"84","article-title":"The pharmacokinetics and pharmacodynamics of monoclonal antibodies \u2013 mechanistic modeling applied to drug development","volume":"10","author":"Mould DR","year":"2007","journal-title":"Curr. Opin. Drug Discov. Dev."},{"key":"e_1_2_5_80_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00512a001"},{"key":"e_1_2_5_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(99)80014-X"},{"key":"e_1_2_5_82_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.30.21037"},{"key":"e_1_2_5_83_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130579"}],"container-title":["Journal of Peptide Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpsc.2782","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psc.2782","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T06:44:47Z","timestamp":1696488287000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/psc.2782"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,5,10]]},"references-count":82,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2015,8]]}},"alternative-id":["10.1002\/psc.2782"],"URL":"https:\/\/doi.org\/10.1002\/psc.2782","archive":["Portico"],"relation":{},"ISSN":["1075-2617","1099-1387"],"issn-type":[{"value":"1075-2617","type":"print"},{"value":"1099-1387","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,5,10]]},"assertion":[{"value":"2015-01-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-03-16","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-05-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}