Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery. / Solbak, Sara Marie Øie; Zang, Jie; Narayanan, Dilip; Høj, Lars Jakobsen; Bucciarelli, Saskia; Softley, Charlotte; Meier, Sebastian; Langkilde, Annette Eva; Gotfredsen, Charlotte Held; Sattler, Michael; Bach, Anders.

In: Journal of Medicinal Chemistry, Vol. 63, No. 3, 2020, p. 1156-1177.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Solbak, SMØ, Zang, J, Narayanan, D, Høj, LJ, Bucciarelli, S, Softley, C, Meier, S, Langkilde, AE, Gotfredsen, CH, Sattler, M & Bach, A 2020, 'Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery', Journal of Medicinal Chemistry, vol. 63, no. 3, pp. 1156-1177. https://doi.org/10.1021/acs.jmedchem.9b01492

APA

Solbak, S. M. Ø., Zang, J., Narayanan, D., Høj, L. J., Bucciarelli, S., Softley, C., Meier, S., Langkilde, A. E., Gotfredsen, C. H., Sattler, M., & Bach, A. (2020). Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery. Journal of Medicinal Chemistry, 63(3), 1156-1177. https://doi.org/10.1021/acs.jmedchem.9b01492

Vancouver

Solbak SMØ, Zang J, Narayanan D, Høj LJ, Bucciarelli S, Softley C et al. Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery. Journal of Medicinal Chemistry. 2020;63(3):1156-1177. https://doi.org/10.1021/acs.jmedchem.9b01492

Author

Solbak, Sara Marie Øie ; Zang, Jie ; Narayanan, Dilip ; Høj, Lars Jakobsen ; Bucciarelli, Saskia ; Softley, Charlotte ; Meier, Sebastian ; Langkilde, Annette Eva ; Gotfredsen, Charlotte Held ; Sattler, Michael ; Bach, Anders. / Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery. In: Journal of Medicinal Chemistry. 2020 ; Vol. 63, No. 3. pp. 1156-1177.

Bibtex

@article{238d53b200af41e5bc47a69016742654,
title = "Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery",
abstract = "NADPH oxidase isoform 2 is an enzyme complex, which generates reactive oxygen species (ROS) and contributes to oxidative stress. The p47phox-p22phox interaction is critical for activation of the catalytical NOX2 domain, and p47phox is a potential target for therapeutic intervention. By screening 2,500 fragments using fluorescence polarization (FP) and a thermal shift assay (TSA) and validation by surface plasmon resonance (SPR) we found eight hits towards the tandem SH3 domain of p47phox (p47phoxSH3A-B) with KD values of 400-600 μM. Structural studies revealed that fragments 1 and 2 bound two separate binding sites in the elongated conformation of p47phoxSH3A-B and these competed with p22phox for binding to p47phoxSH3A-B. Chemical optimization led to a dimeric compound with the ability to potently inhibit the p47phoxSH3A-B-p22phox interaction (Ki of 20 μM). Thereby, we reveal a new way of targeting p47phox and present the first report of druglike molecules able to bind p47phox and inhibit its interaction with p22phox.",
author = "Solbak, {Sara Marie {\O}ie} and Jie Zang and Dilip Narayanan and H{\o}j, {Lars Jakobsen} and Saskia Bucciarelli and Charlotte Softley and Sebastian Meier and Langkilde, {Annette Eva} and Gotfredsen, {Charlotte Held} and Michael Sattler and Anders Bach",
year = "2020",
doi = "10.1021/acs.jmedchem.9b01492",
language = "English",
volume = "63",
pages = "1156--1177",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "3",

}

RIS

TY - JOUR

T1 - Developing Inhibitors of the p47phox-p22phox Protein-Protein Interaction by Fragment-Based Drug Discovery

AU - Solbak, Sara Marie Øie

AU - Zang, Jie

AU - Narayanan, Dilip

AU - Høj, Lars Jakobsen

AU - Bucciarelli, Saskia

AU - Softley, Charlotte

AU - Meier, Sebastian

AU - Langkilde, Annette Eva

AU - Gotfredsen, Charlotte Held

AU - Sattler, Michael

AU - Bach, Anders

PY - 2020

Y1 - 2020

N2 - NADPH oxidase isoform 2 is an enzyme complex, which generates reactive oxygen species (ROS) and contributes to oxidative stress. The p47phox-p22phox interaction is critical for activation of the catalytical NOX2 domain, and p47phox is a potential target for therapeutic intervention. By screening 2,500 fragments using fluorescence polarization (FP) and a thermal shift assay (TSA) and validation by surface plasmon resonance (SPR) we found eight hits towards the tandem SH3 domain of p47phox (p47phoxSH3A-B) with KD values of 400-600 μM. Structural studies revealed that fragments 1 and 2 bound two separate binding sites in the elongated conformation of p47phoxSH3A-B and these competed with p22phox for binding to p47phoxSH3A-B. Chemical optimization led to a dimeric compound with the ability to potently inhibit the p47phoxSH3A-B-p22phox interaction (Ki of 20 μM). Thereby, we reveal a new way of targeting p47phox and present the first report of druglike molecules able to bind p47phox and inhibit its interaction with p22phox.

AB - NADPH oxidase isoform 2 is an enzyme complex, which generates reactive oxygen species (ROS) and contributes to oxidative stress. The p47phox-p22phox interaction is critical for activation of the catalytical NOX2 domain, and p47phox is a potential target for therapeutic intervention. By screening 2,500 fragments using fluorescence polarization (FP) and a thermal shift assay (TSA) and validation by surface plasmon resonance (SPR) we found eight hits towards the tandem SH3 domain of p47phox (p47phoxSH3A-B) with KD values of 400-600 μM. Structural studies revealed that fragments 1 and 2 bound two separate binding sites in the elongated conformation of p47phoxSH3A-B and these competed with p22phox for binding to p47phoxSH3A-B. Chemical optimization led to a dimeric compound with the ability to potently inhibit the p47phoxSH3A-B-p22phox interaction (Ki of 20 μM). Thereby, we reveal a new way of targeting p47phox and present the first report of druglike molecules able to bind p47phox and inhibit its interaction with p22phox.

U2 - 10.1021/acs.jmedchem.9b01492

DO - 10.1021/acs.jmedchem.9b01492

M3 - Journal article

C2 - 31922756

VL - 63

SP - 1156

EP - 1177

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -

ID: 234155458