KEAP1‐NRF2 protein–protein interaction inhibitors: Design, pharmacological properties and therapeutic potential

Crisman, Enrique; Duarte, Pablo Daniel Palacios; Daudén, Esteban; Cuadrado, Antonio; Rodríguez‐Franco, María Isabel; López, Manuela G.; León, Rafael

doi:10.1002/med.21925

Cited by 70 publications

(56 citation statements)

References 141 publications

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“…These molecules are predicted to be safer with respect to electrophilic compounds, whose action is often associated with side-effects due to off-target actions, derived from their simultaneous reaction with different types of nucleophiles commonly present in many biological molecules. Several promising PPI inhibitors have been disclosed to date that are able to enhance Nrf2 signaling with different potential therapeutic applications [ 74 ], and diaryl-azole-based compounds in particular have been demonstrated as useful agents in neurological diseases. Starting from oxadiazole derivatives 9 – 12 ( Figure 10 ) which were able to increase Nrf2 nuclear translocation up to 3.46-fold at 100 nM [ 75 , 76 ], similar triazole derivatives were designed, and compound 13 ( Figure 10 ) was the most interesting one, showing promising results as neuroprotective agents [ 77 , 78 ].…”

Section: Small Molecules Inducing Nrf2mentioning

confidence: 99%

Activators of Nrf2 to Counteract Neurodegenerative Diseases

2023

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Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and loss of nerve cells. Oxidative stress has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders since neuron cells are particularly vulnerable to oxidative damage. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is strictly related to anti-inflammatory and antioxidative cell response; therefore, its activation and the consequent enhancement of the related cellular pathways have been proposed as a potential therapeutic approach. Several Nrf2 activators with different mechanisms and diverse structures have been reported, but those applied for neurodisorders are still limited. However, in the very last few years, interesting progress has been made, particularly in enhancing the blood–brain barrier penetration, to make Nrf2 activators effective drugs, and in designing Nrf2-based multitarget-directed ligands to affect multiple pathways involved in the pathology of neurodegenerative diseases. The present review gives an overview of the most representative findings in this research area.

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Section: Small Molecules Inducing Nrf2mentioning

confidence: 99%

Activators of Nrf2 to Counteract Neurodegenerative Diseases

2023

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“…(iv) Studies on mutations and pharmacological effects demonstrate that inhibiting the low-affinity interaction between the DLG motif of Nrf2 and Keap1 is already sufficient to prevent Nrf2 from being ubiquitinated and to activate the transcription factor [ 66 ].…”

Section: In Silico Prediction Of Bioactive Peptides Dockingmentioning

confidence: 99%

“…This is in favor of electrostatic interactions playing a significant role. The hydrophobic portion of the Keap1-Kelch domain, which is made up of, for example, Phe577, Tyr334 and Tyr572, is also contacted by peptides with the sequences of either the ETGE or the DLG motif [ 66 ].…”

Section: In Silico Prediction Of Bioactive Peptides Dockingmentioning

confidence: 99%

From In Silico to a Cellular Model: Molecular Docking Approach to Evaluate Antioxidant Bioactive Peptides

et al. 2023

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The increasing need to counteract the redox imbalance in chronic diseases leads to focusing research on compounds with antioxidant activity. Among natural molecules with health-promoting effects on many body functions, bioactive peptides are gaining interest. They are protein fragments of 2–20 amino acids that can be released by various mechanisms, such as gastrointestinal digestion, food processing and microbial fermentation. Recent studies report the effects of bioactive peptides in the cellular environment, and there is evidence that these compounds can exert their action by modulating specific pathways. This review focuses on the newest approaches to the structure–function correlation of the antioxidant bioactive peptides, considering their molecular mechanism, by evaluating the activation of specific signaling pathways that are linked to antioxidant systems. The correlation between the results of in silico molecular docking analysis and the effects in a cellular model was highlighted. This knowledge is fundamental in order to propose the use of bioactive peptides as ingredients in functional foods or nutraceuticals.

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“…[53] Each structure reveals three non-covalent binding sites for DMF/fumarate, including two located at the Nrf2-binding interface, the target of numerous inhibitors currently in development. [54] In-cubation of recombinant Keap1-Kelch domain with 1.8-fold excess DMF for 30 minutes inhibits binding of a fluorescein isothiocyanate (FITC)-tagged Nrf2 peptide by ca. 40 %, although there is no evidence that this effect is mediated by non-covalent binding of DMF to Keap1.…”

Section: Structural Basis Of and Putative Insights Into Dimethyl Fuma...mentioning

confidence: 99%

Structural Insights into Electrophiles and Electrophilic Metabolites Sensing and Signaling: The Missing Information

Rogg

Aye

2023

Helvetica Chimica Acta

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Native reactive electrophilic species (RES) are long‐recognized regulators of pathophysiology; yet, knowledge surrounding how RES regulate context‐specific biology remains limited. The latest technological advances in profiling and precision decoding of RES sensing and signaling have begun to bring about improved understanding of localized RES regulatory paradigms. However, studies in purified systems — prerequisites for gaining structure/function insights — prove challenging. We here introduce emerging chemical biology tools available to probe RES signaling, and the new knowledge that these tools have brought to the field. We next discuss existing structural data of RES‐sensor proteins complexed with electrophilic metabolites or small molecule drugs (limited to <300 Da), including challenges faced in acquiring homogenous RES‐bound proteins. We further offer considerations that could promote enhanced understanding of RES regulation derived from three‐dimensional structures of RES‐modified proteins.

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KEAP1‐NRF2 protein–protein interaction inhibitors: Design, pharmacological properties and therapeutic potential

Cited by 70 publications

References 141 publications

Activators of Nrf2 to Counteract Neurodegenerative Diseases

Activators of Nrf2 to Counteract Neurodegenerative Diseases

From In Silico to a Cellular Model: Molecular Docking Approach to Evaluate Antioxidant Bioactive Peptides

Structural Insights into Electrophiles and Electrophilic Metabolites Sensing and Signaling: The Missing Information

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