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Publication Abstract from PubMed

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.

Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction.,Colarusso S, De Simone D, Frattarelli T, Andreini M, Cerretani M, Missineo A, Moretti D, Tambone S, Kempf G, Augustin M, Steinbacher S, Munoz-Sanjuan I, Park L, Summa V, Tomei L, Bresciani A, Dominguez C, Toledo-Sherman L, Bianchi E Bioorg Med Chem. 2020 Aug 30;28(21):115738. doi: 10.1016/j.bmc.2020.115738. PMID:33065433^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.