The Keap1–Nrf2 protein–protein interaction: A suitable target for small molecules

Due to role of the Keap1–Nrf2 protein–protein interaction (PPI) in protecting cells from oxidative stress, the development of small molecule inhibitors that inhibit this interaction has arisen as a viable approach to combat maladies caused by oxidative stress, such as cancers, neurodegenerative disease and diabetes. To obtain specific and genuine Keap1–Nrf2 inhibitors, many efforts have been made towards developing new screening approaches. However, there is no inhibitor for this target entering the clinic for the treatment of human diseases. New strategies to identify novel bioactive compounds from large molecular databases and accelerate the developmental process of the clinical application of Keap1–Nrf2 protein–protein interaction inhibitors are greatly needed. In this review, we have summarized virtual screening and other methods for discovering new lead compounds against the Keap1–Nrf2 protein–protein interaction. We also discuss the advantages and limitations of different strategies, and the potential of this PPI as a drug target in disease therapy.

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Discovery of disubstituted xylylene derivatives as small molecule direct inhibitors of Keap1-Nrf2 protein-protein interaction

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2020.115343 ◽

2020 ◽

Vol 28 (6) ◽

pp. 115343 ◽

Cited By ~ 4

Author(s):

Dhulfiqar Ali Abed ◽

Sumi Lee ◽

Longqin Hu

Keyword(s):

Small Molecule ◽

Protein Interaction ◽

Protein Protein Interaction ◽

Direct Inhibitors ◽

Nrf2 Protein

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Direct inhibition of Keap1-Nrf2 Protein-Protein interaction as a potential therapeutic strategy for Alzheimer's disease

Bioorganic Chemistry ◽

10.1016/j.bioorg.2020.104172 ◽

2020 ◽

Vol 103 ◽

pp. 104172 ◽

Cited By ~ 1

Author(s):

Yi Sun ◽

Jiaxuan Huang ◽

Yufei Chen ◽

Hao Shang ◽

Wannian Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Interaction ◽

Therapeutic Strategy ◽

Direct Inhibition ◽

Protein Protein Interaction ◽

Nrf2 Protein

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Methods for addressing the protein-protein interaction between histone deacetylase 6 and ubiquitin

10.1101/203372 ◽

2017 ◽

Author(s):

Carolina dos S. Passos ◽

Nathalie Deschamps ◽

Yun Choi ◽

Robert E. Cohen ◽

Remo Perozzo ◽

...

Keyword(s):

Catalytic Activity ◽

Stress Response ◽

Small Molecules ◽

Histone Deacetylase ◽

Protein Interaction ◽

Potential Role ◽

Histone Deacetylase 6 ◽

Protein Protein Interaction ◽

Binding Function

AbstractHistone deacetylase 6 (HDAC6) is a cytoplasmic HDAC isoform able to remove acetyl groups from cellular substrates such as α-tubulin. In addition to the two deacetylase domains, HDAC6 has a C-terminal zinc-finger ubiquitin (Ub)-binding domain (ZnF-UBP) able to recognize free Ub. HDAC6-Ub interaction is thought to function in regulating the elimination of misfolded proteins during stress response through the aggresome pathway. Small molecules inhibiting deacetylation by HDAC6 were shown to reduce aggresomes, but the interplay between HDAC6 catalytic activity and Ub-binding function is not fully understood. Here we describe two methods to measure the HDAC6-Ub interaction in vitro using full-length HDAC6. Both methods were effective for screening inhibitors of the HDAC6-Ub protein-protein interaction independently of the catalytic activity. Our results suggest a potential role for the HDAC6 deacetylase domains in modulating HDAC6-Ub interaction. This new aspect of HDAC6 regulation can be targeted to address the roles of HDAC6-Ub interaction in normal and disease conditions.

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