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Solbak, S.M.* ; Zang, J.* ; Narayanan, D.* ; Høj, L.J.* ; Bucciarelli, S.* ; Softley, C. ; Meier, S.* ; Langkilde, A.E.* ; Gotfredsen, C.H.* ; Sattler, M. ; Bach, A.*

Developing inhibitors of the p47phox-p22phox protein-protein interaction by fragment-based drug discovery.

J. Med. Chem. 63, 1156-1177 (2020)
Postprint DOI
Open Access Green
Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 is an enzyme complex, which generates reactive oxygen species and contributes to oxidative stress. The p47phox-p22phox interaction is critical for the activation of the catalytical NOX2 domain, and p47phox is a potential target for therapeutic intervention. By screening 2500 fragments using fluorescence polarization and a thermal shift assay and validation by surface plasmon resonance, we found eight hits toward the tandem SH3 domain of p47phox (p47phox(SH3A-B)) with K-D values of 400-600 mu M. Structural studies revealed that fragments 1 and 2 bound two separate binding sites in the elongated conformation of p47phox(SH3A-B) and these competed with p22phox for binding to p47phox(SH3A-B). Chemical optimization led to a dimeric compound with the ability to potently inhibit the p47phox(SH3A-B)-p22phox interaction (K-i of 20 mu M). Thereby, we reveal a new way of targeting p47phox and present the first report of drug-like molecules with the ability to bind p47phox and inhibit its interaction with p22phox.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Kinetic/affinity Interaction Constants; Phosphorylation-induced Activation; Nadph Oxidase; Diffusion-coefficients; Oxidative Stress; Sh3 Domain; P47(phox); Ebselen; Superoxide; Mechanism
ISSN (print) / ISBN 0022-2623
e-ISSN 1520-4804
Quellenangaben Volume: 63, Issue: 3, Pages: 1156-1177 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Publishing Place 1155 16th St, Nw, Washington, Dc 20036 Usa
Reviewing status Peer reviewed