Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction
[Display omitted] Inhibition of KEAP1-NRF2 protein-protein interaction is considered a promising strategy to selectively and effectively activate NRF2, a transcription factor which is involved in several pathologies such as Huntington’s disease (HD). A library of linear peptides based on the NRF2-bi...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2020-11, Vol.28 (21), p.115738-115738, Article 115738 |
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| creator | Colarusso, Stefania De Simone, Daniele Frattarelli, Tommaso Andreini, Matteo Cerretani, Mauro Missineo, Antonino Moretti, Daniele Tambone, Sara Kempf, Georg Augustin, Martin Steinbacher, Stefan Munoz-Sanjuan, Ignacio Park, Larry Summa, Vincenzo Tomei, Licia Bresciani, Alberto Dominguez, Celia Toledo-Sherman, Leticia Bianchi, Elisabetta |
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Inhibition of KEAP1-NRF2 protein-protein interaction is considered a promising strategy to selectively and effectively activate NRF2, a transcription factor which is involved in several pathologies such as Huntington’s disease (HD). A library of linear peptides based on the NRF2-binding motifs was generated on the nonapeptide lead Ac-LDEETGEFL-NH2 spanning residues 76–84 of the Neh2 domain of NRF2 with the aim to replace E78, E79 and E82 with non-acidic amino acids. A deeper understanding of the features and accessibility of the T80 subpocket was also targeted by structure-based design. Approaches to improve cell permeability were investigated using both different classes of cyclic peptides and conjugation to cell-penetrating peptides. This insight will guide future design of macrocycles, peptido-mimetics and, most importantly, small neutral brain-penetrating molecules to evaluate whether NRF2 activators have utility in HD. |
| doi_str_mv | 10.1016/j.bmc.2020.115738 |
| format | Article |
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Inhibition of KEAP1-NRF2 protein-protein interaction is considered a promising strategy to selectively and effectively activate NRF2, a transcription factor which is involved in several pathologies such as Huntington’s disease (HD). A library of linear peptides based on the NRF2-binding motifs was generated on the nonapeptide lead Ac-LDEETGEFL-NH2 spanning residues 76–84 of the Neh2 domain of NRF2 with the aim to replace E78, E79 and E82 with non-acidic amino acids. A deeper understanding of the features and accessibility of the T80 subpocket was also targeted by structure-based design. Approaches to improve cell permeability were investigated using both different classes of cyclic peptides and conjugation to cell-penetrating peptides. This insight will guide future design of macrocycles, peptido-mimetics and, most importantly, small neutral brain-penetrating molecules to evaluate whether NRF2 activators have utility in HD.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2020.115738</identifier><identifier>PMID: 33065433</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>KEAP1/NRF2 ; Peptide Inhibitors ; PPI</subject><ispartof>Bioorganic & medicinal chemistry, 2020-11, Vol.28 (21), p.115738-115738, Article 115738</ispartof><rights>2020 Elsevier Ltd</rights><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-df3b7d69956a1abbb76afeb608b607ca59e88855b5a848bdf4d9086d65a90de53</citedby><cites>FETCH-LOGICAL-c353t-df3b7d69956a1abbb76afeb608b607ca59e88855b5a848bdf4d9086d65a90de53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2020.115738$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33065433$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Colarusso, Stefania</creatorcontrib><creatorcontrib>De Simone, Daniele</creatorcontrib><creatorcontrib>Frattarelli, Tommaso</creatorcontrib><creatorcontrib>Andreini, Matteo</creatorcontrib><creatorcontrib>Cerretani, Mauro</creatorcontrib><creatorcontrib>Missineo, Antonino</creatorcontrib><creatorcontrib>Moretti, Daniele</creatorcontrib><creatorcontrib>Tambone, Sara</creatorcontrib><creatorcontrib>Kempf, Georg</creatorcontrib><creatorcontrib>Augustin, Martin</creatorcontrib><creatorcontrib>Steinbacher, Stefan</creatorcontrib><creatorcontrib>Munoz-Sanjuan, Ignacio</creatorcontrib><creatorcontrib>Park, Larry</creatorcontrib><creatorcontrib>Summa, Vincenzo</creatorcontrib><creatorcontrib>Tomei, Licia</creatorcontrib><creatorcontrib>Bresciani, Alberto</creatorcontrib><creatorcontrib>Dominguez, Celia</creatorcontrib><creatorcontrib>Toledo-Sherman, Leticia</creatorcontrib><creatorcontrib>Bianchi, Elisabetta</creatorcontrib><title>Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Inhibition of KEAP1-NRF2 protein-protein interaction is considered a promising strategy to selectively and effectively activate NRF2, a transcription factor which is involved in several pathologies such as Huntington’s disease (HD). A library of linear peptides based on the NRF2-binding motifs was generated on the nonapeptide lead Ac-LDEETGEFL-NH2 spanning residues 76–84 of the Neh2 domain of NRF2 with the aim to replace E78, E79 and E82 with non-acidic amino acids. A deeper understanding of the features and accessibility of the T80 subpocket was also targeted by structure-based design. Approaches to improve cell permeability were investigated using both different classes of cyclic peptides and conjugation to cell-penetrating peptides. 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Inhibition of KEAP1-NRF2 protein-protein interaction is considered a promising strategy to selectively and effectively activate NRF2, a transcription factor which is involved in several pathologies such as Huntington’s disease (HD). A library of linear peptides based on the NRF2-binding motifs was generated on the nonapeptide lead Ac-LDEETGEFL-NH2 spanning residues 76–84 of the Neh2 domain of NRF2 with the aim to replace E78, E79 and E82 with non-acidic amino acids. A deeper understanding of the features and accessibility of the T80 subpocket was also targeted by structure-based design. Approaches to improve cell permeability were investigated using both different classes of cyclic peptides and conjugation to cell-penetrating peptides. This insight will guide future design of macrocycles, peptido-mimetics and, most importantly, small neutral brain-penetrating molecules to evaluate whether NRF2 activators have utility in HD.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>33065433</pmid><doi>10.1016/j.bmc.2020.115738</doi><tpages>1</tpages></addata></record> |
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| subjects | KEAP1/NRF2 Peptide Inhibitors PPI |
| title | Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction |
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