{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T11:26:45Z","timestamp":1789212405438,"version":"build-2803163510"},"reference-count":40,"publisher":"National Academy of Sciences","issue":"49","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,12,4]]},"abstract":"<jats:p>\n                    Antibodies hold significant potential for inhibiting toxic protein aggregation associated with conformational disorders such as Alzheimer\u2019s and Huntington\u2019s diseases. However, near-stoichiometric antibody concentrations are typically required to completely inhibit protein aggregation. We posited that the molecular interactions mediating amyloid fibril formation could be harnessed to generate antibodies with potent antiaggregation. Here we report that grafting small amyloidogenic peptides (6\u201310 residues) into the complementarity-determining regions of a single-domain (V\n                    <jats:sub>H<\/jats:sub>\n                    ) antibody yields potent domain antibody inhibitors of amyloid formation. Grafted AMyloid-Motif AntiBODIES (gammabodies) presenting hydrophobic peptides from A\u03b2 (Alzheimer\u2019s disease), \u03b1-Synuclein (Parkinson's disease), and islet amyloid polypeptide (type 2 diabetes) inhibit fibril assembly of each corresponding polypeptide at low substoichiometric concentrations (1:10 gammabody:monomer molar ratio). In contrast, sequence- and conformation-specific antibodies that were obtained via immunization are unable to prevent fibrillization at the same substoichiometric concentrations. Gammabodies prevent amyloid formation by converting monomers and\/or fibrillar intermediates into small complexes that are unstructured and benign. We expect that our antibody design approach\u2014which eliminates the need for immunization or screening to identify sequence-specific domain antibody inhibitors\u2014can be readily extended to generate potent aggregation inhibitors of other amyloidogenic polypeptides linked to human disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1208797109","type":"journal-article","created":{"date-parts":[[2012,11,16]],"date-time":"2012-11-16T20:18:37Z","timestamp":1353097117000},"page":"19965-19970","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":101,"title":["Rational design of potent domain antibody inhibitors of amyloid fibril assembly"],"prefix":"10.1073","volume":"109","author":[{"given":"Ali Reza A.","family":"Ladiwala","sequence":"first","affiliation":[{"name":"Center for Biotechnology and Interdisciplinary Studies, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moumita","family":"Bhattacharya","sequence":"additional","affiliation":[{"name":"Center for Biotechnology and Interdisciplinary Studies, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Perchiacca","sequence":"additional","affiliation":[{"name":"Center for Biotechnology and Interdisciplinary Studies, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Stony Brook University of New York, Stony Brook, NY 11794;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"Raleigh","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Stony Brook University of New York, Stony Brook, NY 11794;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andisheh","family":"Abedini","sequence":"additional","affiliation":[{"name":"Diabetes Research Program, New York University School of Medicine, New York, NY 10016; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Marie","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Diabetes Research Program, New York University School of Medicine, New York, NY 10016; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jobin","family":"Varkey","sequence":"additional","affiliation":[{"name":"Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Langen","sequence":"additional","affiliation":[{"name":"Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA 90033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"Tessier","sequence":"additional","affiliation":[{"name":"Center for Biotechnology and Interdisciplinary Studies, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,11,15]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2011.12.062"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.1.452"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi036281f"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1111232108"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1079469"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-2-18"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.022662599"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708536200"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzs042"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.329763"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1437"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.173856"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.05.144"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M606192200"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi801475r"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M413024200"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1117799109"},{"key":"e_1_3_3_18_2","first-page":"522","article-title":"Islet amyloid polypeptide: Mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus","volume":"66","author":"Johnson KH","year":"1992","unstructured":"KH Johnson, TD O\u2019Brien, C Betsholtz, P Westermark, Islet amyloid polypeptide: Mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus. 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