title: Keap calm, and carry on covalently.
abstract: The Nrf2-Keap1 system plays a major role in cellular defense against oxidative stress. Upon exposure to electrophiles, the cysteine-rich protein Keap1 is covalently modified, and it is this modification of Keap1 that allows the accumulation and subsequent nuclear translocation of Nrf2 where it induces the transcription of over 100 protective genes. This mechanism can be exploited in drug discovery approaches to diseases such as chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), asthma, and neurodegenerative diseases like multiple sclerosis (MS) and Parkinson's, utilizing the modification of Keap1 by electrophiles, compounds that would not normally be considered useful in drug discovery programs. This Perspective discusses the development of potential therapies based on potent electrophiles, such as isothiocyanates and Michael acceptors, that, far from being associated with toxic events, can actually initiate a range of beneficial protective pathways.
authors.affiliation: School of Chemistry, University of Nottingham , University Park, Nottingham NG7 2RD, U.K.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Wilson
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Kerns
authors.forename: James F
authors.initials: JF
authors.lastname: Callahan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Moody
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D055808:Drug Discovery; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D017879:Isothiocyanates / Q000737:chemistry / Q000494:pharmacology; D000072019:Kelch-Like ECH-Associated Protein 1; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013454:Sulfoxides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004952:Esters; D047908:Intracellular Signaling Peptides and Proteins; D017879:Isothiocyanates; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D007659:Ketones; D051267:NF-E2-Related Factor 2; D013454:Sulfoxides; C016766:sulforaphane