Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction.
Bioorg Med Chem
; 28(21): 115738, 2020 11 01.
Article
en En
| MEDLINE
| ID: mdl-33065433
ABSTRACT
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Péptidos
/
Péptidos Cíclicos
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Factor 2 Relacionado con NF-E2
/
Proteína 1 Asociada A ECH Tipo Kelch
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2020
Tipo del documento:
Article