A Macrocyclic Peptide Ligand Binds the Oncogenic MicroRNA-21 Precursor and Suppresses Dicer Processing
MicroRNAs (miRNAs) help orchestrate cellular growth and survival through post-transcriptional mechanisms. The dysregulation of miRNA biogenesis can lead to cellular growth defects and chemotherapeutic resistance and plays a direct role in the development of many chronic diseases. Among these RNAs, m...
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Veröffentlicht in: | ACS chemical biology 2017-06, Vol.12 (6), p.1611-1620 |
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creator | Shortridge, Matthew D Walker, Matthew J Pavelitz, Tom Chen, Yu Yang, Wen Varani, Gabriele |
description | MicroRNAs (miRNAs) help orchestrate cellular growth and survival through post-transcriptional mechanisms. The dysregulation of miRNA biogenesis can lead to cellular growth defects and chemotherapeutic resistance and plays a direct role in the development of many chronic diseases. Among these RNAs, miR-21 is consistently overexpressed in most human cancers, leading to the down-regulation of key tumor-suppressing and pro-apoptotic factors, suggesting that inhibition of miR-21 biogenesis could reverse these negative effects. However, targeted inhibition of miR-21 using small molecules has had limited success. To overcome difficulties in targeting RNA secondary structure with small molecules, we developed a class of cyclic β-hairpin peptidomimetics which bind to RNA stem-loop structures, such as miRNA precursors, with potent affinity and specificity. We screened an existing cyclic peptide library and discovered a lead structure which binds to pre-miR21 with K D = 200 nM and prefers it over other pre-miRNAs. The NMR structure of the complex shows that the peptide recognizes the Dicer cleavage site and alters processing of the precursor to the mature miRNA in vitro and in cultured cells. The structure provides a rationale for the peptide binding activity and clear guidance for further improvements in affinity and targeting. |
doi_str_mv | 10.1021/acschembio.7b00180 |
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The dysregulation of miRNA biogenesis can lead to cellular growth defects and chemotherapeutic resistance and plays a direct role in the development of many chronic diseases. Among these RNAs, miR-21 is consistently overexpressed in most human cancers, leading to the down-regulation of key tumor-suppressing and pro-apoptotic factors, suggesting that inhibition of miR-21 biogenesis could reverse these negative effects. However, targeted inhibition of miR-21 using small molecules has had limited success. To overcome difficulties in targeting RNA secondary structure with small molecules, we developed a class of cyclic β-hairpin peptidomimetics which bind to RNA stem-loop structures, such as miRNA precursors, with potent affinity and specificity. We screened an existing cyclic peptide library and discovered a lead structure which binds to pre-miR21 with K D = 200 nM and prefers it over other pre-miRNAs. The NMR structure of the complex shows that the peptide recognizes the Dicer cleavage site and alters processing of the precursor to the mature miRNA in vitro and in cultured cells. The structure provides a rationale for the peptide binding activity and clear guidance for further improvements in affinity and targeting.</description><identifier>ISSN: 1554-8929</identifier><identifier>EISSN: 1554-8937</identifier><identifier>DOI: 10.1021/acschembio.7b00180</identifier><identifier>PMID: 28437065</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anticarcinogenic Agents - chemistry ; Cell Line ; DEAD-box RNA Helicases - antagonists & inhibitors ; DEAD-box RNA Helicases - metabolism ; Humans ; Ligands ; MicroRNAs - antagonists & inhibitors ; MicroRNAs - metabolism ; Peptide Library ; Peptides, Cyclic - metabolism ; Peptides, Cyclic - pharmacology ; Peptidomimetics - metabolism ; Peptidomimetics - pharmacology ; Protein Binding ; Ribonuclease III - antagonists & inhibitors ; Ribonuclease III - metabolism ; RNA Processing, Post-Transcriptional ; Substrate Specificity</subject><ispartof>ACS chemical biology, 2017-06, Vol.12 (6), p.1611-1620</ispartof><rights>Copyright © 2017 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a441t-bcaeb69f65f4af54d7d07d48a72094e36e25fe5a28c50c32e2bd7168adff3cc33</citedby><cites>FETCH-LOGICAL-a441t-bcaeb69f65f4af54d7d07d48a72094e36e25fe5a28c50c32e2bd7168adff3cc33</cites><orcidid>0000-0003-2825-6836</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acschembio.7b00180$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acschembio.7b00180$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28437065$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shortridge, Matthew D</creatorcontrib><creatorcontrib>Walker, Matthew J</creatorcontrib><creatorcontrib>Pavelitz, Tom</creatorcontrib><creatorcontrib>Chen, Yu</creatorcontrib><creatorcontrib>Yang, Wen</creatorcontrib><creatorcontrib>Varani, Gabriele</creatorcontrib><title>A Macrocyclic Peptide Ligand Binds the Oncogenic MicroRNA-21 Precursor and Suppresses Dicer Processing</title><title>ACS chemical biology</title><addtitle>ACS Chem. Biol</addtitle><description>MicroRNAs (miRNAs) help orchestrate cellular growth and survival through post-transcriptional mechanisms. The dysregulation of miRNA biogenesis can lead to cellular growth defects and chemotherapeutic resistance and plays a direct role in the development of many chronic diseases. Among these RNAs, miR-21 is consistently overexpressed in most human cancers, leading to the down-regulation of key tumor-suppressing and pro-apoptotic factors, suggesting that inhibition of miR-21 biogenesis could reverse these negative effects. However, targeted inhibition of miR-21 using small molecules has had limited success. To overcome difficulties in targeting RNA secondary structure with small molecules, we developed a class of cyclic β-hairpin peptidomimetics which bind to RNA stem-loop structures, such as miRNA precursors, with potent affinity and specificity. We screened an existing cyclic peptide library and discovered a lead structure which binds to pre-miR21 with K D = 200 nM and prefers it over other pre-miRNAs. The NMR structure of the complex shows that the peptide recognizes the Dicer cleavage site and alters processing of the precursor to the mature miRNA in vitro and in cultured cells. The structure provides a rationale for the peptide binding activity and clear guidance for further improvements in affinity and targeting.</description><subject>Animals</subject><subject>Anticarcinogenic Agents - chemistry</subject><subject>Cell Line</subject><subject>DEAD-box RNA Helicases - antagonists & inhibitors</subject><subject>DEAD-box RNA Helicases - metabolism</subject><subject>Humans</subject><subject>Ligands</subject><subject>MicroRNAs - antagonists & inhibitors</subject><subject>MicroRNAs - metabolism</subject><subject>Peptide Library</subject><subject>Peptides, Cyclic - metabolism</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Peptidomimetics - metabolism</subject><subject>Peptidomimetics - pharmacology</subject><subject>Protein Binding</subject><subject>Ribonuclease III - antagonists & inhibitors</subject><subject>Ribonuclease III - metabolism</subject><subject>RNA Processing, Post-Transcriptional</subject><subject>Substrate Specificity</subject><issn>1554-8929</issn><issn>1554-8937</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kV9vFCEUxYnR2Fr9Aj4YHn2ZFRiYYV5M1tpqk61t_PNMGLjs0szCCDNN-u3LZtetvpiQwM39nXPJPQi9pWRBCaMftMlmA9vex0XbE0IleYZOqRC8kl3dPj--WXeCXuV8RwivG9m9RCdM8roljThFbomvtUnRPJjBG3wL4-Qt4JVf62DxJx9sxtMG8E0wcQ2hINe-4N-_LStG8W0CM6ccE97RP-ZxTJAzZPzZG0ilHU2pfVi_Ri-cHjK8Odxn6Nflxc_zr9Xq5svV-XJVac7pVPVGQ990rhGOaye4bS1pLZe6ZaTjUDfAhAOhmTSCmJoB621LG6mtc7UxdX2GPu59x7nfgjUQpqQHNSa_1elBRe3Vv53gN2od75UQlIm2KwbvDwYp_p4hT2rrs4Fh0AHinBWVXTmEy90stkfLPnJO4I5jKFG7gNRTQOoQUBG9-_uDR8mfRAqw2ANFrO7inELZ1_8cHwHVQqC3</recordid><startdate>20170616</startdate><enddate>20170616</enddate><creator>Shortridge, Matthew D</creator><creator>Walker, Matthew J</creator><creator>Pavelitz, Tom</creator><creator>Chen, Yu</creator><creator>Yang, Wen</creator><creator>Varani, Gabriele</creator><general>American Chemical Society</general><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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2825-6836</orcidid></search><sort><creationdate>20170616</creationdate><title>A Macrocyclic Peptide Ligand Binds the Oncogenic MicroRNA-21 Precursor and Suppresses Dicer Processing</title><author>Shortridge, Matthew D ; Walker, Matthew J ; Pavelitz, Tom ; Chen, Yu ; Yang, Wen ; Varani, Gabriele</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a441t-bcaeb69f65f4af54d7d07d48a72094e36e25fe5a28c50c32e2bd7168adff3cc33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Anticarcinogenic Agents - chemistry</topic><topic>Cell Line</topic><topic>DEAD-box RNA Helicases - antagonists & inhibitors</topic><topic>DEAD-box RNA Helicases - metabolism</topic><topic>Humans</topic><topic>Ligands</topic><topic>MicroRNAs - antagonists & inhibitors</topic><topic>MicroRNAs - metabolism</topic><topic>Peptide Library</topic><topic>Peptides, Cyclic - metabolism</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>Peptidomimetics - metabolism</topic><topic>Peptidomimetics - pharmacology</topic><topic>Protein Binding</topic><topic>Ribonuclease III - antagonists & inhibitors</topic><topic>Ribonuclease III - metabolism</topic><topic>RNA Processing, Post-Transcriptional</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shortridge, Matthew D</creatorcontrib><creatorcontrib>Walker, Matthew J</creatorcontrib><creatorcontrib>Pavelitz, Tom</creatorcontrib><creatorcontrib>Chen, Yu</creatorcontrib><creatorcontrib>Yang, Wen</creatorcontrib><creatorcontrib>Varani, Gabriele</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>ACS chemical biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shortridge, Matthew D</au><au>Walker, Matthew J</au><au>Pavelitz, Tom</au><au>Chen, Yu</au><au>Yang, Wen</au><au>Varani, Gabriele</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Macrocyclic Peptide Ligand Binds the Oncogenic MicroRNA-21 Precursor and Suppresses Dicer Processing</atitle><jtitle>ACS chemical biology</jtitle><addtitle>ACS Chem. Biol</addtitle><date>2017-06-16</date><risdate>2017</risdate><volume>12</volume><issue>6</issue><spage>1611</spage><epage>1620</epage><pages>1611-1620</pages><issn>1554-8929</issn><eissn>1554-8937</eissn><abstract>MicroRNAs (miRNAs) help orchestrate cellular growth and survival through post-transcriptional mechanisms. The dysregulation of miRNA biogenesis can lead to cellular growth defects and chemotherapeutic resistance and plays a direct role in the development of many chronic diseases. Among these RNAs, miR-21 is consistently overexpressed in most human cancers, leading to the down-regulation of key tumor-suppressing and pro-apoptotic factors, suggesting that inhibition of miR-21 biogenesis could reverse these negative effects. However, targeted inhibition of miR-21 using small molecules has had limited success. To overcome difficulties in targeting RNA secondary structure with small molecules, we developed a class of cyclic β-hairpin peptidomimetics which bind to RNA stem-loop structures, such as miRNA precursors, with potent affinity and specificity. We screened an existing cyclic peptide library and discovered a lead structure which binds to pre-miR21 with K D = 200 nM and prefers it over other pre-miRNAs. The NMR structure of the complex shows that the peptide recognizes the Dicer cleavage site and alters processing of the precursor to the mature miRNA in vitro and in cultured cells. The structure provides a rationale for the peptide binding activity and clear guidance for further improvements in affinity and targeting.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>28437065</pmid><doi>10.1021/acschembio.7b00180</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-2825-6836</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Anticarcinogenic Agents - chemistry Cell Line DEAD-box RNA Helicases - antagonists & inhibitors DEAD-box RNA Helicases - metabolism Humans Ligands MicroRNAs - antagonists & inhibitors MicroRNAs - metabolism Peptide Library Peptides, Cyclic - metabolism Peptides, Cyclic - pharmacology Peptidomimetics - metabolism Peptidomimetics - pharmacology Protein Binding Ribonuclease III - antagonists & inhibitors Ribonuclease III - metabolism RNA Processing, Post-Transcriptional Substrate Specificity |
title | A Macrocyclic Peptide Ligand Binds the Oncogenic MicroRNA-21 Precursor and Suppresses Dicer Processing |
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