{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T07:59:13Z","timestamp":1791187153897,"version":"4.1.0"},"reference-count":31,"publisher":"National Academy of Sciences","issue":"7","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,2,14]]},"abstract":"<jats:p>\n                    Protein aggregation into cytotoxic oligomers and fibrils\n                    <jats:italic>in vivo<\/jats:italic>\n                    is linked to cell degeneration and the pathogenesis of &gt;25 uncurable diseases, whereas the high aggregation propensity and insolubility of several bioactive polypeptides and proteins\n                    <jats:italic>in vitro<\/jats:italic>\n                    prevent their therapeutic use. Aggregation of human islet amyloid polypeptide (IAPP) into pancreatic amyloid is strongly associated with the pathogenesis of type II diabetes. IAPP is a 37-residue polypeptide that acts as a neuroendocrine regulator of glucose homeostasis. However, IAPP misfolds and self-associates into cytotoxic aggregates and fibrils even at nanomolar concentrations. Because IAPP aggregation causes \u03b2-cell death and prohibits therapeutic application of IAPP in diabetes, we pursued a minimalistic chemical design approach to generate a molecular mimic of a nonamyloidogenic and bioactive IAPP conformation that would still be able to associate with IAPP and thus inhibit its fibrillogenesis and cytotoxicity. We show that the double N-methylated full length IAPP analog [(N-Me)G24, (N-Me)I26]-IAPP (IAPP-GI) is a highly soluble, nonamyloidogenic, and noncytotoxic IAPP molecular mimic and an IAPP receptor agonist. Moreover, IAPP-GI binds IAPP with low nanomolar affinity and completely blocks IAPP cytotoxic self-assembly and fibrillogenesis with activity in the low nanomolar concentration range. Importantly, IAPP-GI dissociates cytotoxic IAPP oligomers and fibrils and is able to reverse their cytotoxicity. Bifunctional soluble IAPP mimics that combine bioactivity with the ability to block and reverse IAPP cytotoxic self-assembly are promising candidates for the treatment of diabetes. Moreover, our amyloid disease inhibitor design concept may be applicable to other protein aggregation diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0507471103","type":"journal-article","created":{"date-parts":[[2006,2,7]],"date-time":"2006-02-07T22:18:40Z","timestamp":1139350720000},"page":"2046-2051","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":240,"title":["Design of a mimic of nonamyloidogenic and bioactive human islet amyloid polypeptide (IAPP) as nanomolar affinity inhibitor of IAPP cytotoxic fibrillogenesis"],"prefix":"10.1073","volume":"103","author":[{"given":"Li-Mei","family":"Yan","sequence":"first","affiliation":[{"name":"Laboratory of Bioorganic and Medicinal Chemistry, Institute of Biochemistry, University Hospital of the Rheinisch\u2013Westf\u00e4lische Technische Hochschule Aachen, Pauwelstrasse 30, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Tatarek-Nossol","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic and Medicinal Chemistry, Institute of Biochemistry, University Hospital of the Rheinisch\u2013Westf\u00e4lische Technische Hochschule Aachen, Pauwelstrasse 30, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Velkova","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic and Medicinal Chemistry, Institute of Biochemistry, University Hospital of the Rheinisch\u2013Westf\u00e4lische Technische Hochschule Aachen, Pauwelstrasse 30, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Kazantzis","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic and Medicinal Chemistry, Institute of Biochemistry, University Hospital of the Rheinisch\u2013Westf\u00e4lische Technische Hochschule Aachen, Pauwelstrasse 30, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aphrodite","family":"Kapurniotu","sequence":"additional","affiliation":[{"name":"Laboratory of Bioorganic and Medicinal Chemistry, Institute of Biochemistry, University Hospital of the Rheinisch\u2013Westf\u00e4lische Technische Hochschule Aachen, Pauwelstrasse 30, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,2,7]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02261"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1007"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.2174\/0929866053005791"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02265"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcibr044231"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568026024607508"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(02)00164-X"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200353565"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2005.05.010"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0405"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0282(2001)60:6<438::AID-BIP10182>3.0.CO;2-A"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevNeurobiol.v11.i2-3.40"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.suppl_3.S233"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1999.2646"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi0160462"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr960387h"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-3233(08)60375-7"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2001.5244"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd939"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.2174\/0929867043364108"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2003.10.009"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1999.3422"},{"key":"e_1_3_3_23_2","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/S0076-6879(99)09020-5","volume-title":"Methods in Enzymology: Amyloid, Prions, and Other Protein Aggregates","author":"LeVine H.","year":"1999","unstructured":"H. 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