{"id":{"repo_id":"aachen","oai_identifier":"oai:publications.rwth-aachen.de:63211"},"canonical_url":"https://search.dev.ndltd.org/etd/aachen/oai:publications.rwth-aachen.de:63211","repository":{"repo_id":"aachen","name":"RWTH Aachen University","base_url":"https://publications.rwth-aachen.de/oai2d"},"display":{"title":"Identification and charaeterization of IAPP-derived inhibitors of cytotoxic self-assembly and amyloidogenesis of islet amyloid polypeptide (IAPP) and beta-amyloid peptide (A beta)","abstract":"Protein aggregation into cytotoxic oligomers and fibrils in vivo is linked to cell degeneration and the pathogenesis of more than 25 uncurable diseases, which are often called amyloid diseases, while the high aggregation propensity and insolubility of several bioactive polypeptides and proteins in vitro prevents their therapeutic use. Aggregation of human islet amyloid polypeptide (IAPP) into pancreatic amyloid is strongly associated with pancreatic cell-degeneration and the pathogenesis of type II diabetes (T2D). IAPP is a 37-residue polypeptide which acts physiologically as a neuroendocrine regulator of glucose homeostasis. However, IAPP misfolds and self-associates into cytotoxic aggregates and fibrils even at nanomolar concentrations. Brain amyloid plaque formation, cell degeneration and the pathogenesis of Alzheimer’s disease (AD) are associated with cytotoxic misfolding and self-assembly of ß-amyloid peptide (Aß). Aß is a ubiquitary expressed, 40 (Aß(1-40)) to 42 (Aß(1-42)) residue polypeptide of yet unknown physiological function. Aß is found in serum and cerebrospinalfluid in subnanomolar concentration. Both Aß and IAPP are short, natively unfolded polypeptides which share a sequence similarity of 50% but have been so far thought to be functionally unrelated. Clinical and pathophysiological observations indicate that the two major cell degenerative diseases AD and T2D might be linked to each other. However, direct evidence for a molecular link has been missing. Compounds that block cytotoxic protein/polypeptide self-assembly and amyloidogenesis are important targets of therapeutic intervention in protein aggregation diseases. The concept underlying the here presented studies was based on the hypothesis that bifunctional soluble IAPP mimics which combine bioactivity with the ability to block and reverse IAPP cytotoxic self-assembly could be promising candidates for treatment of diabetes. Using a recently developed minimalistic conformational restriction strategy, four double N-methylated IAPP analogues, [(N-Me)G24, (N-Me)I26]-IAPP (IAPP-GI), [(N-Me)A25, (N-Me)L27]-IAPP (IAPP-LA), [(N-Me)F23, (N-Me)A25]-IAPP (IAPP-FA) and [(N-Me)I26, (N-Me)L27]-IAPP (IAPP-LI), have been designed and synthesized. Their design approach was based on the hypothesis that NFGAIL is a crucial “amyloid core” and self-recognition sequence of IAPP and consisted of the introduction of two N-methyl residues into selected amide bonds within the NFGAIL region of full length IAPP. In fact, the studies presented in this thesis show that these four IAPP analogues are highly soluble, non-amyloidogenic, and non-cytotoxic molecular analogues of a non-amyloidogenic IAPP conformation and full IAPP receptor agonists. In addition, the studies show that all four designed IAPP analogues are able to interact with IAPP and to suppress IAPP cytotoxic self-assembly and fibrillogenesis. The potencies of the effects of the different IAPP analogues differ significantly, consistent with a conformational specificity of the IAPP-analogue interaction causing their inhibitory effects. Most importantly, it is also shown that all four analogues are able to interfere with Aß(1-40) and to suppress with varying potencies Aß(1-40) self-assembly and fibrillogenesis. Thereby, IAPP-GI is proved to be the most potent analogue with regard to inhibition of self-assembly of both IAPP and Aß(1-40). These findings suggest that IAPP-GI and/or the other IAPP analogues might become lead compounds for the development of therapeutics in T2D and/or AD. In addition, the studies presented in this thesis also suggest that hetero-association of early prefibrillar and likely non-toxic IAPP and Aß(1-40) species into soluble hetero-complexes attenuates cytotoxic self-association of both polypeptides. Hetero-association of early prefibrillar and nontoxic IAPP and Aß(1-40) species may “protect” both polypeptides from pathogenic misfolding and self-association in vivo, offering thus a molecular link between the pathogenesis of AD and T2D and suggesting that effective therapeutic strategies targeting both diseases might be possible. Taken together, the results in this thesis offer a proof-of-principle of a novel concept for designing potent amyloid disease therapeutics and of a chemical engineering approach to redesign a natively amyloidogenic and bioactive polypeptide sequence into a soluble, non-cytotoxic, and bioactive analogue which is also a highly potent inhibitor of cytotoxic self-assembly of the native amyloidogenic sequence it has been derived from. Therefore, the inhibitor design concept tested in this thesis might applicable to other disease-related self-associating polypeptides too.","abstract_html":"Protein aggregation into cytotoxic oligomers and fibrils in vivo is linked to cell degeneration and the pathogenesis of more than 25 uncurable diseases, which are often called amyloid diseases, while the high aggregation propensity and insolubility of several bioactive polypeptides and proteins in vitro prevents their therapeutic use. Aggregation of human islet amyloid polypeptide (IAPP) into pancreatic amyloid is strongly associated with pancreatic cell-degeneration and the pathogenesis of type II diabetes (T2D). IAPP is a 37-residue polypeptide which acts physiologically as a neuroendocrine regulator of glucose homeostasis. However, IAPP misfolds and self-associates into cytotoxic aggregates and fibrils even at nanomolar concentrations. Brain amyloid plaque formation, cell degeneration and the pathogenesis of Alzheimer’s disease (AD) are associated with cytotoxic misfolding and self-assembly of ß-amyloid peptide (Aß). Aß is a ubiquitary expressed, 40 (Aß(1-40)) to 42 (Aß(1-42)) residue polypeptide of yet unknown physiological function. Aß is found in serum and cerebrospinalfluid in subnanomolar concentration. Both Aß and IAPP are short, natively unfolded polypeptides which share a sequence similarity of 50% but have been so far thought to be functionally unrelated. Clinical and pathophysiological observations indicate that the two major cell degenerative diseases AD and T2D might be linked to each other. However, direct evidence for a molecular link has been missing. Compounds that block cytotoxic protein/polypeptide self-assembly and amyloidogenesis are important targets of therapeutic intervention in protein aggregation diseases. The concept underlying the here presented studies was based on the hypothesis that bifunctional soluble IAPP mimics which combine bioactivity with the ability to block and reverse IAPP cytotoxic self-assembly could be promising candidates for treatment of diabetes. Using a recently developed minimalistic conformational restriction strategy, four double N-methylated IAPP analogues, [(N-Me)G24, (N-Me)I26]-IAPP (IAPP-GI), [(N-Me)A25, (N-Me)L27]-IAPP (IAPP-LA), [(N-Me)F23, (N-Me)A25]-IAPP (IAPP-FA) and [(N-Me)I26, (N-Me)L27]-IAPP (IAPP-LI), have been designed and synthesized. Their design approach was based on the hypothesis that NFGAIL is a crucial “amyloid core” and self-recognition sequence of IAPP and consisted of the introduction of two N-methyl residues into selected amide bonds within the NFGAIL region of full length IAPP. In fact, the studies presented in this thesis show that these four IAPP analogues are highly soluble, non-amyloidogenic, and non-cytotoxic molecular analogues of a non-amyloidogenic IAPP conformation and full IAPP receptor agonists. In addition, the studies show that all four designed IAPP analogues are able to interact with IAPP and to suppress IAPP cytotoxic self-assembly and fibrillogenesis. The potencies of the effects of the different IAPP analogues differ significantly, consistent with a conformational specificity of the IAPP-analogue interaction causing their inhibitory effects. Most importantly, it is also shown that all four analogues are able to interfere with Aß(1-40) and to suppress with varying potencies Aß(1-40) self-assembly and fibrillogenesis. Thereby, IAPP-GI is proved to be the most potent analogue with regard to inhibition of self-assembly of both IAPP and Aß(1-40). These findings suggest that IAPP-GI and/or the other IAPP analogues might become lead compounds for the development of therapeutics in T2D and/or AD. In addition, the studies presented in this thesis also suggest that hetero-association of early prefibrillar and likely non-toxic IAPP and Aß(1-40) species into soluble hetero-complexes attenuates cytotoxic self-association of both polypeptides. Hetero-association of early prefibrillar and nontoxic IAPP and Aß(1-40) species may “protect” both polypeptides from pathogenic misfolding and self-association in vivo, offering thus a molecular link between the pathogenesis of AD and T2D and suggesting that effective therapeutic strategies targeting both diseases might be possible. Taken together, the results in this thesis offer a proof-of-principle of a novel concept for designing potent amyloid disease therapeutics and of a chemical engineering approach to redesign a natively amyloidogenic and bioactive polypeptide sequence into a soluble, non-cytotoxic, and bioactive analogue which is also a highly potent inhibitor of cytotoxic self-assembly of the native amyloidogenic sequence it has been derived from. Therefore, the inhibitor design concept tested in this thesis might applicable to other disease-related self-associating polypeptides too.","abstract_has_math":false,"creators":["Yan, Li-Mei"],"institution":"Publikationsserver der RWTH Aachen University","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Kapurniotu, Aphrodite","Baumgartner, Werner"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2008,"date_issued":"2008","date_published":"2008","updated_at":"2026-07-30T19:43:35Z","subjects":["info:eu-repo/classification/ddc/570","Amylin","Amyloid-Peptid <beta->","Diabetes","Alzheimer-Krankheit","Inhibitor","Biowissenschaften, Biologie","Selbstassoziation","Amyloidfibrillen","protein aggregation","amyloidogenesis inhibitor","protein design"],"languages":["eng"],"rights":["info:eu-repo/semantics/openAccess"],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-124658%22"],"render_values":[{"text":"https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-124658%22","href":"https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-124658%22","code":true}]}]},"links":{"outbound_url":"https://publications.rwth-aachen.de/record/63211","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Kapurniotu, Aphrodite","Baumgartner, Werner"]},{"key":"dc:creator","label":"Author","values":["Yan, Li-Mei"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:coverage","label":"Dc Coverage","values":["DE"]},{"key":"dc:date","label":"Dc Date","values":["2008"]},{"key":"dc:publisher","label":"Institution","values":["Publikationsserver der RWTH Aachen University"]},{"key":"dc:relation","label":"Dc Relation","values":["info:eu-repo/semantics/altIdentifier/urn/urn:nbn:de:hbz:82-opus-29420"]},{"key":"dc:type","label":"Dc Type","values":["info:eu-repo/semantics/doctoralThesis","info:eu-repo/semantics/publishedVersion"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["info:eu-repo/classification/ddc/570","Amylin","Amyloid-Peptid <beta->","Diabetes","Alzheimer-Krankheit","Inhibitor","Biowissenschaften, Biologie","Selbstassoziation","Amyloidfibrillen","protein aggregation","amyloidogenesis inhibitor","protein design"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["info:eu-repo/semantics/openAccess"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://publications.rwth-aachen.de/record/63211","https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-124658%22"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Protein aggregation into cytotoxic oligomers and fibrils in vivo is linked to cell degeneration and the pathogenesis of more than 25 uncurable diseases, which are often called amyloid diseases, while the high aggregation propensity and insolubility of several bioactive polypeptides and proteins in vitro prevents their therapeutic use. Aggregation of human islet amyloid polypeptide (IAPP) into pancreatic amyloid is strongly associated with pancreatic cell-degeneration and the pathogenesis of type II diabetes (T2D). IAPP is a 37-residue polypeptide which acts physiologically as a neuroendocrine regulator of glucose homeostasis. However, IAPP misfolds and self-associates into cytotoxic aggregates and fibrils even at nanomolar concentrations. Brain amyloid plaque formation, cell degeneration and the pathogenesis of Alzheimer’s disease (AD) are associated with cytotoxic misfolding and self-assembly of ß-amyloid peptide (Aß). Aß is a ubiquitary expressed, 40 (Aß(1-40)) to 42 (Aß(1-42)) residue polypeptide of yet unknown physiological function. Aß is found in serum and cerebrospinalfluid in subnanomolar concentration. Both Aß and IAPP are short, natively unfolded polypeptides which share a sequence similarity of 50% but have been so far thought to be functionally unrelated. Clinical and pathophysiological observations indicate that the two major cell degenerative diseases AD and T2D might be linked to each other. However, direct evidence for a molecular link has been missing. Compounds that block cytotoxic protein/polypeptide self-assembly and amyloidogenesis are important targets of therapeutic intervention in protein aggregation diseases. The concept underlying the here presented studies was based on the hypothesis that bifunctional soluble IAPP mimics which combine bioactivity with the ability to block and reverse IAPP cytotoxic self-assembly could be promising candidates for treatment of diabetes. Using a recently developed minimalistic conformational restriction strategy, four double N-methylated IAPP analogues, [(N-Me)G24, (N-Me)I26]-IAPP (IAPP-GI), [(N-Me)A25, (N-Me)L27]-IAPP (IAPP-LA), [(N-Me)F23, (N-Me)A25]-IAPP (IAPP-FA) and [(N-Me)I26, (N-Me)L27]-IAPP (IAPP-LI), have been designed and synthesized. Their design approach was based on the hypothesis that NFGAIL is a crucial “amyloid core” and self-recognition sequence of IAPP and consisted of the introduction of two N-methyl residues into selected amide bonds within the NFGAIL region of full length IAPP. In fact, the studies presented in this thesis show that these four IAPP analogues are highly soluble, non-amyloidogenic, and non-cytotoxic molecular analogues of a non-amyloidogenic IAPP conformation and full IAPP receptor agonists. In addition, the studies show that all four designed IAPP analogues are able to interact with IAPP and to suppress IAPP cytotoxic self-assembly and fibrillogenesis. The potencies of the effects of the different IAPP analogues differ significantly, consistent with a conformational specificity of the IAPP-analogue interaction causing their inhibitory effects. Most importantly, it is also shown that all four analogues are able to interfere with Aß(1-40) and to suppress with varying potencies Aß(1-40) self-assembly and fibrillogenesis. Thereby, IAPP-GI is proved to be the most potent analogue with regard to inhibition of self-assembly of both IAPP and Aß(1-40). These findings suggest that IAPP-GI and/or the other IAPP analogues might become lead compounds for the development of therapeutics in T2D and/or AD. In addition, the studies presented in this thesis also suggest that hetero-association of early prefibrillar and likely non-toxic IAPP and Aß(1-40) species into soluble hetero-complexes attenuates cytotoxic self-association of both polypeptides. Hetero-association of early prefibrillar and nontoxic IAPP and Aß(1-40) species may “protect” both polypeptides from pathogenic misfolding and self-association in vivo, offering thus a molecular link between the pathogenesis of AD and T2D and suggesting that effective therapeutic strategies targeting both diseases might be possible. Taken together, the results in this thesis offer a proof-of-principle of a novel concept for designing potent amyloid disease therapeutics and of a chemical engineering approach to redesign a natively amyloidogenic and bioactive polypeptide sequence into a soluble, non-cytotoxic, and bioactive analogue which is also a highly potent inhibitor of cytotoxic self-assembly of the native amyloidogenic sequence it has been derived from. Therefore, the inhibitor design concept tested in this thesis might applicable to other disease-related self-associating polypeptides too."]},{"key":"dc:source","label":"Dc Source","values":["Aachen : Publikationsserver der RWTH Aachen University XI, 149 Bl. : Ill., graph. Darst. (2008). = Aachen, Techn. Hochsch., Diss., 2008"]},{"key":"dc:title","label":"Title","values":["Identification and charaeterization of IAPP-derived inhibitors of cytotoxic self-assembly and amyloidogenesis of islet amyloid polypeptide (IAPP) and beta-amyloid peptide (A beta)"]}]}],"canonical_facts":{"dc:contributor":["Kapurniotu, Aphrodite","Baumgartner, Werner"],"dc:coverage":["DE"],"dc:creator":["Yan, Li-Mei"],"dc:date":["2008"],"dc:description":["Protein aggregation into cytotoxic oligomers and fibrils in vivo is linked to cell degeneration and the pathogenesis of more than 25 uncurable diseases, which are often called amyloid diseases, while the high aggregation propensity and insolubility of several bioactive polypeptides and proteins in vitro prevents their therapeutic use. Aggregation of human islet amyloid polypeptide (IAPP) into pancreatic amyloid is strongly associated with pancreatic cell-degeneration and the pathogenesis of type II diabetes (T2D). IAPP is a 37-residue polypeptide which acts physiologically as a neuroendocrine regulator of glucose homeostasis. However, IAPP misfolds and self-associates into cytotoxic aggregates and fibrils even at nanomolar concentrations. Brain amyloid plaque formation, cell degeneration and the pathogenesis of Alzheimer’s disease (AD) are associated with cytotoxic misfolding and self-assembly of ß-amyloid peptide (Aß). Aß is a ubiquitary expressed, 40 (Aß(1-40)) to 42 (Aß(1-42)) residue polypeptide of yet unknown physiological function. Aß is found in serum and cerebrospinalfluid in subnanomolar concentration. Both Aß and IAPP are short, natively unfolded polypeptides which share a sequence similarity of 50% but have been so far thought to be functionally unrelated. Clinical and pathophysiological observations indicate that the two major cell degenerative diseases AD and T2D might be linked to each other. However, direct evidence for a molecular link has been missing. Compounds that block cytotoxic protein/polypeptide self-assembly and amyloidogenesis are important targets of therapeutic intervention in protein aggregation diseases. The concept underlying the here presented studies was based on the hypothesis that bifunctional soluble IAPP mimics which combine bioactivity with the ability to block and reverse IAPP cytotoxic self-assembly could be promising candidates for treatment of diabetes. Using a recently developed minimalistic conformational restriction strategy, four double N-methylated IAPP analogues, [(N-Me)G24, (N-Me)I26]-IAPP (IAPP-GI), [(N-Me)A25, (N-Me)L27]-IAPP (IAPP-LA), [(N-Me)F23, (N-Me)A25]-IAPP (IAPP-FA) and [(N-Me)I26, (N-Me)L27]-IAPP (IAPP-LI), have been designed and synthesized. Their design approach was based on the hypothesis that NFGAIL is a crucial “amyloid core” and self-recognition sequence of IAPP and consisted of the introduction of two N-methyl residues into selected amide bonds within the NFGAIL region of full length IAPP. In fact, the studies presented in this thesis show that these four IAPP analogues are highly soluble, non-amyloidogenic, and non-cytotoxic molecular analogues of a non-amyloidogenic IAPP conformation and full IAPP receptor agonists. In addition, the studies show that all four designed IAPP analogues are able to interact with IAPP and to suppress IAPP cytotoxic self-assembly and fibrillogenesis. The potencies of the effects of the different IAPP analogues differ significantly, consistent with a conformational specificity of the IAPP-analogue interaction causing their inhibitory effects. Most importantly, it is also shown that all four analogues are able to interfere with Aß(1-40) and to suppress with varying potencies Aß(1-40) self-assembly and fibrillogenesis. Thereby, IAPP-GI is proved to be the most potent analogue with regard to inhibition of self-assembly of both IAPP and Aß(1-40). These findings suggest that IAPP-GI and/or the other IAPP analogues might become lead compounds for the development of therapeutics in T2D and/or AD. In addition, the studies presented in this thesis also suggest that hetero-association of early prefibrillar and likely non-toxic IAPP and Aß(1-40) species into soluble hetero-complexes attenuates cytotoxic self-association of both polypeptides. Hetero-association of early prefibrillar and nontoxic IAPP and Aß(1-40) species may “protect” both polypeptides from pathogenic misfolding and self-association in vivo, offering thus a molecular link between the pathogenesis of AD and T2D and suggesting that effective therapeutic strategies targeting both diseases might be possible. Taken together, the results in this thesis offer a proof-of-principle of a novel concept for designing potent amyloid disease therapeutics and of a chemical engineering approach to redesign a natively amyloidogenic and bioactive polypeptide sequence into a soluble, non-cytotoxic, and bioactive analogue which is also a highly potent inhibitor of cytotoxic self-assembly of the native amyloidogenic sequence it has been derived from. Therefore, the inhibitor design concept tested in this thesis might applicable to other disease-related self-associating polypeptides too."],"dc:identifier":["https://publications.rwth-aachen.de/record/63211","https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-124658%22"],"dc:language":["eng"],"dc:publisher":["Publikationsserver der RWTH Aachen University"],"dc:relation":["info:eu-repo/semantics/altIdentifier/urn/urn:nbn:de:hbz:82-opus-29420"],"dc:rights":["info:eu-repo/semantics/openAccess"],"dc:source":["Aachen : Publikationsserver der RWTH Aachen University XI, 149 Bl. : Ill., graph. Darst. (2008). = Aachen, Techn. 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