Keap1 Knockdown Tackles Allergic Rhinitis

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https://doi.org/10.1016/j.apsb.2025.05.025

This new article publication from Acta Pharmaceutica Sinica B, discusses the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.

Allergic rhinitis (AR), a globally prevalent immune-mediated inflammatory condition, is still an incurable disease. The authors of this article validated the impact of the Kelch-like ECH associated protein 1 (Keap1)-related oxidative stress and inflammatory response in clinical AR patient peripheral blood and nasal swab samples, emphasizing the biological relevance of Keap1 and AR. Targeting Keap1 -nuclear factor erythroid 2-related factor 2 (Nrf2) related anti-oxidative stress may be effective for AR intervention. Drawing inspiration from the Keap1 homodimerization and the E3 ligase characteristics, a design of novel bivalent molecules for chemical knockdown of Keap1 is presented. For the first time, ternary complexes of Keap1 dimer and one molecule of bivalent compounds are characterized. The best bivalent molecule 8 encompasses robust capacity to degrade Keap1 as a homoPROTACKEAP1. It efficaciously suppresses inflammatory cytokines in extensively different cells, including human nasal epithelial cells. Moreover, in an AR mouse model, it was confirmed that the chemical degradation induced by homoPROTACKEAP1 led to therapeutic benefits in managing AR symptoms, oxidative stress and inflammation. In summary, these findings underscore the efficacy of targeting the Keap1 system through the homoPROTAC-ing technology as an innovative and promising treatment strategy for the incurable allergic disorders.

Keywords: Allergic rhinitis, Keap1, Nrf2, E3 ligase, Degradation, HomoPROTAC

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525003314-ga1_lrg.jpg

A new divalent molecule was designed to target the Keap1 system through homoPROTAC-ing technology as an innovative and promising strategy for the treatment of AR.

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