Engineered coiled-coil HIF1α protein domain mimic
The development of targeted anti-cancer therapeutics offers the potential for increased efficacy of drugs and diagnostics. Utilizing modalities agnostic to tumor type, such as the hypoxic tumor microenvironment (TME), may assist in the development of universal tumor targeting agents. The hypoxia-ind...
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| Veröffentlicht in: | Biomaterials science 2024-05, Vol.12 (11), p.2951-2959 |
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| creator | Britton, Dustin Katsara, Olga Mishkit, Orin Wang, Andrew Pandya, Neelam Liu, Chengliang Mao, Heather Legocki, Jakub Jia, Sihan Xiao, Yingxin Aristizabal, Orlando Paul, Deven Deng, Yan Schneider, Robert Wadghiri, Youssef Z Montclare, Jin Kim |
| description | The development of targeted anti-cancer therapeutics offers the potential for increased efficacy of drugs and diagnostics. Utilizing modalities agnostic to tumor type, such as the hypoxic tumor microenvironment (TME), may assist in the development of universal tumor targeting agents. The hypoxia-inducible factor (HIF), in particular HIF1, plays a key role in tumor adaptation to hypoxia, and inhibiting its interaction with p300 has been shown to provide therapeutic potential. Using a multivalent assembled protein (MAP) approach based on the self-assembly of the cartilage oligomeric matrix protein coiled-coil (COMPcc) domain fused to the critical residues of the C-terminal transactivation domain (C-TAD) of the α subunit of HIF1 (HIF1α), we generate HIF1α-MAP (H-MAP). The resulting H-MAP demonstrates picomolar binding affinity to p300, the ability to downregulate hypoxia-inducible genes, and
in vivo
tumor targeting capability.
Multivalent assembled proteins (MAPs) as protein domain mimics (PDMs) of HIF1α allows for improved tumor targeting. |
| doi_str_mv | 10.1039/d4bm00354c |
| format | Article |
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in vivo
tumor targeting capability.
Multivalent assembled proteins (MAPs) as protein domain mimics (PDMs) of HIF1α allows for improved tumor targeting.</description><identifier>ISSN: 2047-4830</identifier><identifier>ISSN: 2047-4849</identifier><identifier>EISSN: 2047-4849</identifier><identifier>DOI: 10.1039/d4bm00354c</identifier><identifier>PMID: 38656316</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Animals ; Cartilage Oligomeric Matrix Protein - chemistry ; Cartilage Oligomeric Matrix Protein - metabolism ; Cell Line, Tumor ; Coils ; E1A-Associated p300 Protein - chemistry ; E1A-Associated p300 Protein - metabolism ; Humans ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit - chemistry ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Mice ; Protein Domains ; Protein Engineering ; Proteins ; Self-assembly ; Tumor Microenvironment ; Tumors</subject><ispartof>Biomaterials science, 2024-05, Vol.12 (11), p.2951-2959</ispartof><rights>Copyright Royal Society of Chemistry 2024</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c296t-c7eb1806cbb793e03bbfe9ed8e57b0eb6f3c74953117ff80c308f5e6c4258c3c3</cites><orcidid>0000-0001-6857-3591</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38656316$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Britton, Dustin</creatorcontrib><creatorcontrib>Katsara, Olga</creatorcontrib><creatorcontrib>Mishkit, Orin</creatorcontrib><creatorcontrib>Wang, Andrew</creatorcontrib><creatorcontrib>Pandya, Neelam</creatorcontrib><creatorcontrib>Liu, Chengliang</creatorcontrib><creatorcontrib>Mao, Heather</creatorcontrib><creatorcontrib>Legocki, Jakub</creatorcontrib><creatorcontrib>Jia, Sihan</creatorcontrib><creatorcontrib>Xiao, Yingxin</creatorcontrib><creatorcontrib>Aristizabal, Orlando</creatorcontrib><creatorcontrib>Paul, Deven</creatorcontrib><creatorcontrib>Deng, Yan</creatorcontrib><creatorcontrib>Schneider, Robert</creatorcontrib><creatorcontrib>Wadghiri, Youssef Z</creatorcontrib><creatorcontrib>Montclare, Jin Kim</creatorcontrib><title>Engineered coiled-coil HIF1α protein domain mimic</title><title>Biomaterials science</title><addtitle>Biomater Sci</addtitle><description>The development of targeted anti-cancer therapeutics offers the potential for increased efficacy of drugs and diagnostics. Utilizing modalities agnostic to tumor type, such as the hypoxic tumor microenvironment (TME), may assist in the development of universal tumor targeting agents. The hypoxia-inducible factor (HIF), in particular HIF1, plays a key role in tumor adaptation to hypoxia, and inhibiting its interaction with p300 has been shown to provide therapeutic potential. Using a multivalent assembled protein (MAP) approach based on the self-assembly of the cartilage oligomeric matrix protein coiled-coil (COMPcc) domain fused to the critical residues of the C-terminal transactivation domain (C-TAD) of the α subunit of HIF1 (HIF1α), we generate HIF1α-MAP (H-MAP). The resulting H-MAP demonstrates picomolar binding affinity to p300, the ability to downregulate hypoxia-inducible genes, and
in vivo
tumor targeting capability.
Multivalent assembled proteins (MAPs) as protein domain mimics (PDMs) of HIF1α allows for improved tumor targeting.</description><subject>Animals</subject><subject>Cartilage Oligomeric Matrix Protein - chemistry</subject><subject>Cartilage Oligomeric Matrix Protein - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Coils</subject><subject>E1A-Associated p300 Protein - chemistry</subject><subject>E1A-Associated p300 Protein - metabolism</subject><subject>Humans</subject><subject>Hypoxia</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - chemistry</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</subject><subject>Mice</subject><subject>Protein Domains</subject><subject>Protein Engineering</subject><subject>Proteins</subject><subject>Self-assembly</subject><subject>Tumor Microenvironment</subject><subject>Tumors</subject><issn>2047-4830</issn><issn>2047-4849</issn><issn>2047-4849</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1Lw0AQhhdRbKm9eFcCXkSIzmY_c9TaaqHiRc8hu5lISj7qbnPwZ_lH_E1uba3gMPAOzMPw8g4hpxSuKbD0puCmAWCC2wMyTICrmGueHu5nBgMy9n4JoZRKQdJjMmBaCsmoHJJk2r5VLaLDIrJdVWMRbyR6nM_o12e0ct0aqzYquiYP0lRNZU_IUZnXHsc7HZHX2fRl8hgvnh_mk9tFbJNUrmOr0FAN0hqjUobAjCkxxUKjUAbQyJJZxVPBKFVlqcEy0KVAaXkitGWWjcjl9m4w8d6jX2dN5S3Wdd5i1_uMAZeCUq15QC_-ocuud21wFygJSgoWekSutpR1nfcOy2zlqiZ3HxmFbBNmds_vnn7CnAT4fHeyNw0We_Q3ugCcbQHn7X779w32DczMdwU</recordid><startdate>20240528</startdate><enddate>20240528</enddate><creator>Britton, Dustin</creator><creator>Katsara, Olga</creator><creator>Mishkit, Orin</creator><creator>Wang, Andrew</creator><creator>Pandya, Neelam</creator><creator>Liu, Chengliang</creator><creator>Mao, Heather</creator><creator>Legocki, Jakub</creator><creator>Jia, Sihan</creator><creator>Xiao, Yingxin</creator><creator>Aristizabal, Orlando</creator><creator>Paul, Deven</creator><creator>Deng, Yan</creator><creator>Schneider, Robert</creator><creator>Wadghiri, Youssef Z</creator><creator>Montclare, Jin Kim</creator><general>Royal Society of Chemistry</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>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6857-3591</orcidid></search><sort><creationdate>20240528</creationdate><title>Engineered coiled-coil HIF1α protein domain mimic</title><author>Britton, Dustin ; Katsara, Olga ; Mishkit, Orin ; Wang, Andrew ; Pandya, Neelam ; Liu, Chengliang ; Mao, Heather ; Legocki, Jakub ; Jia, Sihan ; Xiao, Yingxin ; Aristizabal, Orlando ; Paul, Deven ; Deng, Yan ; Schneider, Robert ; Wadghiri, Youssef Z ; Montclare, Jin Kim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c296t-c7eb1806cbb793e03bbfe9ed8e57b0eb6f3c74953117ff80c308f5e6c4258c3c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Cartilage Oligomeric Matrix Protein - chemistry</topic><topic>Cartilage Oligomeric Matrix Protein - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Coils</topic><topic>E1A-Associated p300 Protein - chemistry</topic><topic>E1A-Associated p300 Protein - metabolism</topic><topic>Humans</topic><topic>Hypoxia</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - chemistry</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</topic><topic>Mice</topic><topic>Protein Domains</topic><topic>Protein Engineering</topic><topic>Proteins</topic><topic>Self-assembly</topic><topic>Tumor Microenvironment</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Britton, Dustin</creatorcontrib><creatorcontrib>Katsara, Olga</creatorcontrib><creatorcontrib>Mishkit, Orin</creatorcontrib><creatorcontrib>Wang, Andrew</creatorcontrib><creatorcontrib>Pandya, Neelam</creatorcontrib><creatorcontrib>Liu, Chengliang</creatorcontrib><creatorcontrib>Mao, Heather</creatorcontrib><creatorcontrib>Legocki, Jakub</creatorcontrib><creatorcontrib>Jia, Sihan</creatorcontrib><creatorcontrib>Xiao, Yingxin</creatorcontrib><creatorcontrib>Aristizabal, Orlando</creatorcontrib><creatorcontrib>Paul, Deven</creatorcontrib><creatorcontrib>Deng, Yan</creatorcontrib><creatorcontrib>Schneider, Robert</creatorcontrib><creatorcontrib>Wadghiri, Youssef Z</creatorcontrib><creatorcontrib>Montclare, Jin Kim</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>MEDLINE - Academic</collection><jtitle>Biomaterials science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Britton, Dustin</au><au>Katsara, Olga</au><au>Mishkit, Orin</au><au>Wang, Andrew</au><au>Pandya, Neelam</au><au>Liu, Chengliang</au><au>Mao, Heather</au><au>Legocki, Jakub</au><au>Jia, Sihan</au><au>Xiao, Yingxin</au><au>Aristizabal, Orlando</au><au>Paul, Deven</au><au>Deng, Yan</au><au>Schneider, Robert</au><au>Wadghiri, Youssef Z</au><au>Montclare, Jin Kim</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Engineered coiled-coil HIF1α protein domain mimic</atitle><jtitle>Biomaterials science</jtitle><addtitle>Biomater Sci</addtitle><date>2024-05-28</date><risdate>2024</risdate><volume>12</volume><issue>11</issue><spage>2951</spage><epage>2959</epage><pages>2951-2959</pages><issn>2047-4830</issn><issn>2047-4849</issn><eissn>2047-4849</eissn><abstract>The development of targeted anti-cancer therapeutics offers the potential for increased efficacy of drugs and diagnostics. Utilizing modalities agnostic to tumor type, such as the hypoxic tumor microenvironment (TME), may assist in the development of universal tumor targeting agents. The hypoxia-inducible factor (HIF), in particular HIF1, plays a key role in tumor adaptation to hypoxia, and inhibiting its interaction with p300 has been shown to provide therapeutic potential. Using a multivalent assembled protein (MAP) approach based on the self-assembly of the cartilage oligomeric matrix protein coiled-coil (COMPcc) domain fused to the critical residues of the C-terminal transactivation domain (C-TAD) of the α subunit of HIF1 (HIF1α), we generate HIF1α-MAP (H-MAP). The resulting H-MAP demonstrates picomolar binding affinity to p300, the ability to downregulate hypoxia-inducible genes, and
in vivo
tumor targeting capability.
Multivalent assembled proteins (MAPs) as protein domain mimics (PDMs) of HIF1α allows for improved tumor targeting.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>38656316</pmid><doi>10.1039/d4bm00354c</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-6857-3591</orcidid></addata></record> |
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| source | MEDLINE; Royal Society Of Chemistry Journals 2008- |
| subjects | Animals Cartilage Oligomeric Matrix Protein - chemistry Cartilage Oligomeric Matrix Protein - metabolism Cell Line, Tumor Coils E1A-Associated p300 Protein - chemistry E1A-Associated p300 Protein - metabolism Humans Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit - chemistry Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Mice Protein Domains Protein Engineering Proteins Self-assembly Tumor Microenvironment Tumors |
| title | Engineered coiled-coil HIF1α protein domain mimic |
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