Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction.

Autor: Colarusso S; Department of Drug Discovery, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy. Electronic address: s.colarusso@irbm.com., De Simone D; Department of Drug Discovery, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Frattarelli T; Department of Drug Discovery, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Andreini M; Department of Drug Discovery, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Cerretani M; Translational & Discovery Research, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Missineo A; Translational & Discovery Research, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Moretti D; Translational & Discovery Research, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Tambone S; Translational & Discovery Research, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Kempf G; Proteros Biostructures GmbH, Bunsenstraße 7 a, 82152 Planegg, Germany., Augustin M; Proteros Biostructures GmbH, Bunsenstraße 7 a, 82152 Planegg, Germany., Steinbacher S; Proteros Biostructures GmbH, Bunsenstraße 7 a, 82152 Planegg, Germany., Munoz-Sanjuan I; CHDI Management/CHDI Foundation, Los Angeles, CA, United States., Park L; CHDI Management/CHDI Foundation, Los Angeles, CA, United States., Summa V; Department of Drug Discovery, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Tomei L; Translational & Discovery Research, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Bresciani A; Translational & Discovery Research, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Dominguez C; CHDI Management/CHDI Foundation, Los Angeles, CA, United States. Electronic address: celia.dominguez@chdifoundation.org., Toledo-Sherman L; Translational & Discovery Research, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy., Bianchi E; Department of Drug Discovery, IRBM Spa, Via Pontina km 30.600, 00071 Pomezia, Rome, Italy.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Nov 01; Vol. 28 (21), pp. 115738. Date of Electronic Publication: 2020 Aug 30.
DOI: 10.1016/j.bmc.2020.115738
Abstrakt: 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-NH 2 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.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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