The Human Host‐Defense Peptide Cathelicidin LL‐37 is a Nanomolar Inhibitor of Amyloid Self‐Assembly of Islet Amyloid Polypeptide (IAPP)
Amyloid self‐assembly of islet amyloid polypeptide (IAPP) is linked to pancreatic inflammation, β‐cell degeneration, and the pathogenesis of type 2 diabetes (T2D). The multifunctional host‐defence peptides (HDPs) cathelicidins play crucial roles in inflammation. Here, we show that the antimicrobial...
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| Veröffentlicht in: | Angewandte Chemie International Edition 2020-07, Vol.59 (31), p.12837-12841 |
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| creator | Armiento, Valentina Hille, Kathleen Naltsas, Denise Lin, Jennifer S. Barron, Annelise E. Kapurniotu, Aphrodite |
| description | Amyloid self‐assembly of islet amyloid polypeptide (IAPP) is linked to pancreatic inflammation, β‐cell degeneration, and the pathogenesis of type 2 diabetes (T2D). The multifunctional host‐defence peptides (HDPs) cathelicidins play crucial roles in inflammation. Here, we show that the antimicrobial and immunomodulatory polypeptide human cathelicidin LL‐37 binds IAPP with nanomolar affinity and effectively suppresses its amyloid self‐assembly and related pancreatic β‐cell damage in vitro. In addition, we identify key LL‐37 segments that mediate its interaction with IAPP. Our results suggest a possible protective role for LL‐37 in T2D pathogenesis and offer a molecular basis for the design of LL‐37‐derived peptides that combine antimicrobial, immunomodulatory, and T2D‐related anti‐amyloid functions as promising candidates for multifunctional drugs.
One for all: A high‐affinity amyloid‐suppressing interaction between the human antimicrobial and immunomodulatory polypeptide cathelicidin LL‐37 and the key type 2 diabetes (T2D) amyloid polypeptide IAPP was identified. The results suggest a protective role for LL‐37 in T2D pathogenesis and offer a molecular basis for the design of novel molecules combining antimicrobial, immunomodulatory, and anti‐amyloid functions as multifunctional drug candidates. |
| doi_str_mv | 10.1002/anie.202000148 |
| format | Article |
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One for all: A high‐affinity amyloid‐suppressing interaction between the human antimicrobial and immunomodulatory polypeptide cathelicidin LL‐37 and the key type 2 diabetes (T2D) amyloid polypeptide IAPP was identified. The results suggest a protective role for LL‐37 in T2D pathogenesis and offer a molecular basis for the design of novel molecules combining antimicrobial, immunomodulatory, and anti‐amyloid functions as multifunctional drug candidates.</description><edition>International ed. in English</edition><identifier>ISSN: 1433-7851</identifier><identifier>ISSN: 1521-3773</identifier><identifier>EISSN: 1521-3773</identifier><identifier>DOI: 10.1002/anie.202000148</identifier><identifier>PMID: 31999880</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Amino Acid Sequence ; Amylin ; Amyloid ; amyloids ; Antiinfectives and antibacterials ; Antimicrobial Cationic Peptides - metabolism ; Assembly ; Beta cells ; Cathelicidins ; Communication ; Communications ; Degeneration ; Diabetes mellitus (non-insulin dependent) ; Drug development ; Humans ; Immunomodulation ; inhibitors ; Islet Amyloid Polypeptide - chemistry ; Islet Amyloid Polypeptide - metabolism ; Pancreas ; Pathogenesis ; Peptide Fragments - metabolism ; Peptides ; Polypeptides ; Protein Binding ; protein interactions ; Protein Multimerization - drug effects ; self-assembly ; type 2 diabetes</subject><ispartof>Angewandte Chemie International Edition, 2020-07, Vol.59 (31), p.12837-12841</ispartof><rights>2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.</rights><rights>2020. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5718-949ee4af3ad161d4b9a3024393f77070544b47dc287e8b694036bde287b9dd243</citedby><cites>FETCH-LOGICAL-c5718-949ee4af3ad161d4b9a3024393f77070544b47dc287e8b694036bde287b9dd243</cites><orcidid>0000-0001-6124-7232</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fanie.202000148$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fanie.202000148$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31999880$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Armiento, Valentina</creatorcontrib><creatorcontrib>Hille, Kathleen</creatorcontrib><creatorcontrib>Naltsas, Denise</creatorcontrib><creatorcontrib>Lin, Jennifer S.</creatorcontrib><creatorcontrib>Barron, Annelise E.</creatorcontrib><creatorcontrib>Kapurniotu, Aphrodite</creatorcontrib><title>The Human Host‐Defense Peptide Cathelicidin LL‐37 is a Nanomolar Inhibitor of Amyloid Self‐Assembly of Islet Amyloid Polypeptide (IAPP)</title><title>Angewandte Chemie International Edition</title><addtitle>Angew Chem Int Ed Engl</addtitle><description>Amyloid self‐assembly of islet amyloid polypeptide (IAPP) is linked to pancreatic inflammation, β‐cell degeneration, and the pathogenesis of type 2 diabetes (T2D). The multifunctional host‐defence peptides (HDPs) cathelicidins play crucial roles in inflammation. Here, we show that the antimicrobial and immunomodulatory polypeptide human cathelicidin LL‐37 binds IAPP with nanomolar affinity and effectively suppresses its amyloid self‐assembly and related pancreatic β‐cell damage in vitro. In addition, we identify key LL‐37 segments that mediate its interaction with IAPP. Our results suggest a possible protective role for LL‐37 in T2D pathogenesis and offer a molecular basis for the design of LL‐37‐derived peptides that combine antimicrobial, immunomodulatory, and T2D‐related anti‐amyloid functions as promising candidates for multifunctional drugs.
One for all: A high‐affinity amyloid‐suppressing interaction between the human antimicrobial and immunomodulatory polypeptide cathelicidin LL‐37 and the key type 2 diabetes (T2D) amyloid polypeptide IAPP was identified. The results suggest a protective role for LL‐37 in T2D pathogenesis and offer a molecular basis for the design of novel molecules combining antimicrobial, immunomodulatory, and anti‐amyloid functions as multifunctional drug candidates.</description><subject>Amino Acid Sequence</subject><subject>Amylin</subject><subject>Amyloid</subject><subject>amyloids</subject><subject>Antiinfectives and antibacterials</subject><subject>Antimicrobial Cationic Peptides - metabolism</subject><subject>Assembly</subject><subject>Beta cells</subject><subject>Cathelicidins</subject><subject>Communication</subject><subject>Communications</subject><subject>Degeneration</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Drug development</subject><subject>Humans</subject><subject>Immunomodulation</subject><subject>inhibitors</subject><subject>Islet Amyloid Polypeptide - chemistry</subject><subject>Islet Amyloid Polypeptide - metabolism</subject><subject>Pancreas</subject><subject>Pathogenesis</subject><subject>Peptide Fragments - metabolism</subject><subject>Peptides</subject><subject>Polypeptides</subject><subject>Protein Binding</subject><subject>protein interactions</subject><subject>Protein Multimerization - drug effects</subject><subject>self-assembly</subject><subject>type 2 diabetes</subject><issn>1433-7851</issn><issn>1521-3773</issn><issn>1521-3773</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNqFkcuO0zAUhiMEYoaBLUtkic2wSPEtcbxBispAI1VDJYa15SQn1CPHLnECyo4XGGmekSfBVUu5bFj5WOfzd3z0J8lzghcEY_paOwMLiinGmPDiQXJOMkpSJgR7GGvOWCqKjJwlT0K4jXxR4PxxcsaIlDLW58ndzRbQauq1Qysfxh_f799CBy4A2sBuNC2gpR63YE1jWuPQeh0JJpAJSKNr7XzvrR5Q5bamNqMfkO9Q2c_WmxZ9BNtFugwB-trO-1YVLIwnYOPtvDtOuazKzebV0-RRp22AZ8fzIvn07upmuUrXH95Xy3KdNpkgRSq5BOC6Y7olOWl5LTXDlDPJOiGwwBnnNRdtQwsBRZ1LjlletxCvtWzbCF4kbw7e3VT30DbgxkFbtRtMr4dZeW3U3x1ntuqz_6oElwKTPAouj4LBf5kgjKo3oQFrtQM_BUVZhrEsKGYRffkPeuunwcX1FOU0yzKecRmpxYFqBh_CAN3pMwSrfdJqn7Q6JR0fvPhzhRP-K9oIyAPwzViY_6NT5XV19Vv-E9PCt78</recordid><startdate>20200727</startdate><enddate>20200727</enddate><creator>Armiento, Valentina</creator><creator>Hille, Kathleen</creator><creator>Naltsas, Denise</creator><creator>Lin, Jennifer S.</creator><creator>Barron, Annelise E.</creator><creator>Kapurniotu, Aphrodite</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6124-7232</orcidid></search><sort><creationdate>20200727</creationdate><title>The Human Host‐Defense Peptide Cathelicidin LL‐37 is a Nanomolar Inhibitor of Amyloid Self‐Assembly of Islet Amyloid Polypeptide (IAPP)</title><author>Armiento, Valentina ; Hille, Kathleen ; Naltsas, Denise ; Lin, Jennifer S. ; Barron, Annelise E. ; Kapurniotu, Aphrodite</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5718-949ee4af3ad161d4b9a3024393f77070544b47dc287e8b694036bde287b9dd243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Amino Acid Sequence</topic><topic>Amylin</topic><topic>Amyloid</topic><topic>amyloids</topic><topic>Antiinfectives and antibacterials</topic><topic>Antimicrobial Cationic Peptides - metabolism</topic><topic>Assembly</topic><topic>Beta cells</topic><topic>Cathelicidins</topic><topic>Communication</topic><topic>Communications</topic><topic>Degeneration</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Drug development</topic><topic>Humans</topic><topic>Immunomodulation</topic><topic>inhibitors</topic><topic>Islet Amyloid Polypeptide - chemistry</topic><topic>Islet Amyloid Polypeptide - metabolism</topic><topic>Pancreas</topic><topic>Pathogenesis</topic><topic>Peptide Fragments - metabolism</topic><topic>Peptides</topic><topic>Polypeptides</topic><topic>Protein Binding</topic><topic>protein interactions</topic><topic>Protein Multimerization - drug effects</topic><topic>self-assembly</topic><topic>type 2 diabetes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Armiento, Valentina</creatorcontrib><creatorcontrib>Hille, Kathleen</creatorcontrib><creatorcontrib>Naltsas, Denise</creatorcontrib><creatorcontrib>Lin, Jennifer S.</creatorcontrib><creatorcontrib>Barron, Annelise E.</creatorcontrib><creatorcontrib>Kapurniotu, Aphrodite</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Angewandte Chemie International Edition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Armiento, Valentina</au><au>Hille, Kathleen</au><au>Naltsas, Denise</au><au>Lin, Jennifer S.</au><au>Barron, Annelise E.</au><au>Kapurniotu, Aphrodite</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Human Host‐Defense Peptide Cathelicidin LL‐37 is a Nanomolar Inhibitor of Amyloid Self‐Assembly of Islet Amyloid Polypeptide (IAPP)</atitle><jtitle>Angewandte Chemie International Edition</jtitle><addtitle>Angew Chem Int Ed Engl</addtitle><date>2020-07-27</date><risdate>2020</risdate><volume>59</volume><issue>31</issue><spage>12837</spage><epage>12841</epage><pages>12837-12841</pages><issn>1433-7851</issn><issn>1521-3773</issn><eissn>1521-3773</eissn><abstract>Amyloid self‐assembly of islet amyloid polypeptide (IAPP) is linked to pancreatic inflammation, β‐cell degeneration, and the pathogenesis of type 2 diabetes (T2D). The multifunctional host‐defence peptides (HDPs) cathelicidins play crucial roles in inflammation. Here, we show that the antimicrobial and immunomodulatory polypeptide human cathelicidin LL‐37 binds IAPP with nanomolar affinity and effectively suppresses its amyloid self‐assembly and related pancreatic β‐cell damage in vitro. In addition, we identify key LL‐37 segments that mediate its interaction with IAPP. Our results suggest a possible protective role for LL‐37 in T2D pathogenesis and offer a molecular basis for the design of LL‐37‐derived peptides that combine antimicrobial, immunomodulatory, and T2D‐related anti‐amyloid functions as promising candidates for multifunctional drugs.
One for all: A high‐affinity amyloid‐suppressing interaction between the human antimicrobial and immunomodulatory polypeptide cathelicidin LL‐37 and the key type 2 diabetes (T2D) amyloid polypeptide IAPP was identified. The results suggest a protective role for LL‐37 in T2D pathogenesis and offer a molecular basis for the design of novel molecules combining antimicrobial, immunomodulatory, and anti‐amyloid functions as multifunctional drug candidates.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>31999880</pmid><doi>10.1002/anie.202000148</doi><tpages>5</tpages><edition>International ed. in English</edition><orcidid>https://orcid.org/0000-0001-6124-7232</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Amino Acid Sequence Amylin Amyloid amyloids Antiinfectives and antibacterials Antimicrobial Cationic Peptides - metabolism Assembly Beta cells Cathelicidins Communication Communications Degeneration Diabetes mellitus (non-insulin dependent) Drug development Humans Immunomodulation inhibitors Islet Amyloid Polypeptide - chemistry Islet Amyloid Polypeptide - metabolism Pancreas Pathogenesis Peptide Fragments - metabolism Peptides Polypeptides Protein Binding protein interactions Protein Multimerization - drug effects self-assembly type 2 diabetes |
| title | The Human Host‐Defense Peptide Cathelicidin LL‐37 is a Nanomolar Inhibitor of Amyloid Self‐Assembly of Islet Amyloid Polypeptide (IAPP) |
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