Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors

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

Standard

Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors. / Voss, Jan H.; Crüsemann, Max; Bartling, Christian R.O.; Kehraus, Stefan; Inoue, Asuka; König, Gabriele M.; Strømgaard, Kristian; Müller, Christa E.

In: iScience, Vol. 26, No. 4, 106492, 2023.

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

Harvard

Voss, JH, Crüsemann, M, Bartling, CRO, Kehraus, S, Inoue, A, König, GM, Strømgaard, K & Müller, CE 2023, 'Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors', iScience, vol. 26, no. 4, 106492. https://doi.org/10.1016/j.isci.2023.106492

APA

Voss, J. H., Crüsemann, M., Bartling, C. R. O., Kehraus, S., Inoue, A., König, G. M., Strømgaard, K., & Müller, C. E. (2023). Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors. iScience, 26(4), [106492]. https://doi.org/10.1016/j.isci.2023.106492

Vancouver

Voss JH, Crüsemann M, Bartling CRO, Kehraus S, Inoue A, König GM et al. Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors. iScience. 2023;26(4). 106492. https://doi.org/10.1016/j.isci.2023.106492

Author

Voss, Jan H. ; Crüsemann, Max ; Bartling, Christian R.O. ; Kehraus, Stefan ; Inoue, Asuka ; König, Gabriele M. ; Strømgaard, Kristian ; Müller, Christa E. / Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors. In: iScience. 2023 ; Vol. 26, No. 4.

Bibtex

@article{964ee55ed0a44b959e7456ecd853fa03,
title = "Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors",
abstract = "The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gαq/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled Gq protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic Gq protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome.",
keywords = "Biochemistry, Biological sciences, Pharmacology",
author = "Voss, {Jan H.} and Max Cr{\"u}semann and Bartling, {Christian R.O.} and Stefan Kehraus and Asuka Inoue and K{\"o}nig, {Gabriele M.} and Kristian Str{\o}mgaard and M{\"u}ller, {Christa E.}",
note = "Funding Information: This study was supported with a research grant from the Deutsche Forschungsgemeinschaft ( FOR2372 ; MU1665/7-2 ), the Open Access Publication Fund of the University of Bonn , and the Bonn International Graduate School of Drug Sciences. A.I. was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI grants 21H04791 , 21H05113 and JPJSBP120213501, and the Japan Science and Technology Agency (JST) grant JPMJFR215T . Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
doi = "10.1016/j.isci.2023.106492",
language = "English",
volume = "26",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier",
number = "4",

}

RIS

TY - JOUR

T1 - Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors

AU - Voss, Jan H.

AU - Crüsemann, Max

AU - Bartling, Christian R.O.

AU - Kehraus, Stefan

AU - Inoue, Asuka

AU - König, Gabriele M.

AU - Strømgaard, Kristian

AU - Müller, Christa E.

N1 - Funding Information: This study was supported with a research grant from the Deutsche Forschungsgemeinschaft ( FOR2372 ; MU1665/7-2 ), the Open Access Publication Fund of the University of Bonn , and the Bonn International Graduate School of Drug Sciences. A.I. was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI grants 21H04791 , 21H05113 and JPJSBP120213501, and the Japan Science and Technology Agency (JST) grant JPMJFR215T . Publisher Copyright: © 2023 The Authors

PY - 2023

Y1 - 2023

N2 - The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gαq/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled Gq protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic Gq protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome.

AB - The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gαq/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled Gq protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic Gq protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome.

KW - Biochemistry

KW - Biological sciences

KW - Pharmacology

U2 - 10.1016/j.isci.2023.106492

DO - 10.1016/j.isci.2023.106492

M3 - Journal article

C2 - 37091255

AN - SCOPUS:85154024221

VL - 26

JO - iScience

JF - iScience

SN - 2589-0042

IS - 4

M1 - 106492

ER -

ID: 346408022