Targeting NOX2 with Bivalent Small-Molecule p47phox-p22phox Inhibitors

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

Standard

Targeting NOX2 with Bivalent Small-Molecule p47phox-p22phox Inhibitors. / Zang, Jie; Peters, Felix; Cambet, Yves; Cifuentes-Pagano, Eugenia; Hissabu, Munira Mohamed Shishay; Dustin, Christopher M; Svensson, Lars Henrik; Olesen, Martin Mariboe; Poulsen, Mathias Feldt Lomholt; Jacobsen, Stig; Tuelung, Pernille Sønderby; Narayanan, Dilip; Langkilde, Annette Eva; Gajhede, Michael; Pagano, Patrick J; Jaquet, Vincent; Vilhardt, Frederik; Bach, Anders.

In: Journal of Medicinal Chemistry, Vol. 66, No. 21, 2023, p. 14963–15005.

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

Harvard

Zang, J, Peters, F, Cambet, Y, Cifuentes-Pagano, E, Hissabu, MMS, Dustin, CM, Svensson, LH, Olesen, MM, Poulsen, MFL, Jacobsen, S, Tuelung, PS, Narayanan, D, Langkilde, AE, Gajhede, M, Pagano, PJ, Jaquet, V, Vilhardt, F & Bach, A 2023, 'Targeting NOX2 with Bivalent Small-Molecule p47phox-p22phox Inhibitors', Journal of Medicinal Chemistry, vol. 66, no. 21, pp. 14963–15005. https://doi.org/10.1021/acs.jmedchem.3c01548

APA

Zang, J., Peters, F., Cambet, Y., Cifuentes-Pagano, E., Hissabu, M. M. S., Dustin, C. M., Svensson, L. H., Olesen, M. M., Poulsen, M. F. L., Jacobsen, S., Tuelung, P. S., Narayanan, D., Langkilde, A. E., Gajhede, M., Pagano, P. J., Jaquet, V., Vilhardt, F., & Bach, A. (2023). Targeting NOX2 with Bivalent Small-Molecule p47phox-p22phox Inhibitors. Journal of Medicinal Chemistry, 66(21), 14963–15005. https://doi.org/10.1021/acs.jmedchem.3c01548

Vancouver

Zang J, Peters F, Cambet Y, Cifuentes-Pagano E, Hissabu MMS, Dustin CM et al. Targeting NOX2 with Bivalent Small-Molecule p47phox-p22phox Inhibitors. Journal of Medicinal Chemistry. 2023;66(21):14963–15005. https://doi.org/10.1021/acs.jmedchem.3c01548

Author

Zang, Jie ; Peters, Felix ; Cambet, Yves ; Cifuentes-Pagano, Eugenia ; Hissabu, Munira Mohamed Shishay ; Dustin, Christopher M ; Svensson, Lars Henrik ; Olesen, Martin Mariboe ; Poulsen, Mathias Feldt Lomholt ; Jacobsen, Stig ; Tuelung, Pernille Sønderby ; Narayanan, Dilip ; Langkilde, Annette Eva ; Gajhede, Michael ; Pagano, Patrick J ; Jaquet, Vincent ; Vilhardt, Frederik ; Bach, Anders. / Targeting NOX2 with Bivalent Small-Molecule p47phox-p22phox Inhibitors. In: Journal of Medicinal Chemistry. 2023 ; Vol. 66, No. 21. pp. 14963–15005.

Bibtex

@article{af91a90c037a41daa780ff59d227d7f4,
title = "Targeting NOX2 with Bivalent Small-Molecule p47phox-p22phox Inhibitors",
abstract = "Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) is an enzymatic complex whose function is the regulated generation of reactive oxygen species (ROS). NOX2 activity is central to redox signaling events and antibacterial response, but excessive ROS production by NOX2 leads to oxidative stress and inflammation in a range of diseases. The protein-protein interaction between the NOX2 subunits p47phox and p22phox is essential for NOX2 activation, thus p47phox is a potential drug target. Previously, we identified 2-aminoquinoline as a fragment hit toward p47phox SH3A-B and converted it to a bivalent small-molecule p47phox-p22phox inhibitor ( K i = 20 μM). Here, we systematically optimized the bivalent compounds by exploring linker types and positioning as well as substituents on the 2-aminoquinoline part and characterized the bivalent binding mode with biophysical methods. We identified several compounds with submicromolar binding affinities and cellular activity and thereby demonstrated that p47phox can be targeted by potent small molecules. ",
author = "Jie Zang and Felix Peters and Yves Cambet and Eugenia Cifuentes-Pagano and Hissabu, {Munira Mohamed Shishay} and Dustin, {Christopher M} and Svensson, {Lars Henrik} and Olesen, {Martin Mariboe} and Poulsen, {Mathias Feldt Lomholt} and Stig Jacobsen and Tuelung, {Pernille S{\o}nderby} and Dilip Narayanan and Langkilde, {Annette Eva} and Michael Gajhede and Pagano, {Patrick J} and Vincent Jaquet and Frederik Vilhardt and Anders Bach",
year = "2023",
doi = "10.1021/acs.jmedchem.3c01548",
language = "English",
volume = "66",
pages = "14963–15005",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "21",

}

RIS

TY - JOUR

T1 - Targeting NOX2 with Bivalent Small-Molecule p47phox-p22phox Inhibitors

AU - Zang, Jie

AU - Peters, Felix

AU - Cambet, Yves

AU - Cifuentes-Pagano, Eugenia

AU - Hissabu, Munira Mohamed Shishay

AU - Dustin, Christopher M

AU - Svensson, Lars Henrik

AU - Olesen, Martin Mariboe

AU - Poulsen, Mathias Feldt Lomholt

AU - Jacobsen, Stig

AU - Tuelung, Pernille Sønderby

AU - Narayanan, Dilip

AU - Langkilde, Annette Eva

AU - Gajhede, Michael

AU - Pagano, Patrick J

AU - Jaquet, Vincent

AU - Vilhardt, Frederik

AU - Bach, Anders

PY - 2023

Y1 - 2023

N2 - Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) is an enzymatic complex whose function is the regulated generation of reactive oxygen species (ROS). NOX2 activity is central to redox signaling events and antibacterial response, but excessive ROS production by NOX2 leads to oxidative stress and inflammation in a range of diseases. The protein-protein interaction between the NOX2 subunits p47phox and p22phox is essential for NOX2 activation, thus p47phox is a potential drug target. Previously, we identified 2-aminoquinoline as a fragment hit toward p47phox SH3A-B and converted it to a bivalent small-molecule p47phox-p22phox inhibitor ( K i = 20 μM). Here, we systematically optimized the bivalent compounds by exploring linker types and positioning as well as substituents on the 2-aminoquinoline part and characterized the bivalent binding mode with biophysical methods. We identified several compounds with submicromolar binding affinities and cellular activity and thereby demonstrated that p47phox can be targeted by potent small molecules.

AB - Nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) is an enzymatic complex whose function is the regulated generation of reactive oxygen species (ROS). NOX2 activity is central to redox signaling events and antibacterial response, but excessive ROS production by NOX2 leads to oxidative stress and inflammation in a range of diseases. The protein-protein interaction between the NOX2 subunits p47phox and p22phox is essential for NOX2 activation, thus p47phox is a potential drug target. Previously, we identified 2-aminoquinoline as a fragment hit toward p47phox SH3A-B and converted it to a bivalent small-molecule p47phox-p22phox inhibitor ( K i = 20 μM). Here, we systematically optimized the bivalent compounds by exploring linker types and positioning as well as substituents on the 2-aminoquinoline part and characterized the bivalent binding mode with biophysical methods. We identified several compounds with submicromolar binding affinities and cellular activity and thereby demonstrated that p47phox can be targeted by potent small molecules.

U2 - 10.1021/acs.jmedchem.3c01548

DO - 10.1021/acs.jmedchem.3c01548

M3 - Journal article

C2 - 37857466

VL - 66

SP - 14963

EP - 15005

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 21

ER -

ID: 370662952