Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors

Research output: Contribution to journalJournal article

Standard

Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors. / Maric, Hans-Michael; Kasaragod, Vikram Babu; Kedström, Linda Maria Haugaard; Hausrat, Torben Johann; Kneussel, Matthias; Schindelin, Hermann; Strømgaard, Kristian.

In: Angewandte Chemie (International ed. in English), Vol. 54, No. 2, 07.01.2015, p. 490-4.

Research output: Contribution to journalJournal article

Harvard

Maric, H-M, Kasaragod, VB, Kedström, LMH, Hausrat, TJ, Kneussel, M, Schindelin, H & Strømgaard, K 2015, 'Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors', Angewandte Chemie (International ed. in English), vol. 54, no. 2, pp. 490-4. https://doi.org/10.1002/anie.201409043

APA

Maric, H-M., Kasaragod, V. B., Kedström, L. M. H., Hausrat, T. J., Kneussel, M., Schindelin, H., & Strømgaard, K. (2015). Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors. Angewandte Chemie (International ed. in English), 54(2), 490-4. https://doi.org/10.1002/anie.201409043

Vancouver

Maric H-M, Kasaragod VB, Kedström LMH, Hausrat TJ, Kneussel M, Schindelin H et al. Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors. Angewandte Chemie (International ed. in English). 2015 Jan 7;54(2):490-4. https://doi.org/10.1002/anie.201409043

Author

Maric, Hans-Michael ; Kasaragod, Vikram Babu ; Kedström, Linda Maria Haugaard ; Hausrat, Torben Johann ; Kneussel, Matthias ; Schindelin, Hermann ; Strømgaard, Kristian. / Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors. In: Angewandte Chemie (International ed. in English). 2015 ; Vol. 54, No. 2. pp. 490-4.

Bibtex

@article{3c6a43f54e014f7cb00808d0d0922bd7,
title = "Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors",
abstract = "Gephyrin is the central scaffolding protein for inhibitory neurotransmitter receptors in the brain. Here we describe the development of dimeric peptides that inhibit the interaction between gephyrin and these receptors, a process which is fundamental to numerous synaptic functions and diseases of the brain. We first identified receptor-derived minimal gephyrin-binding peptides that displayed exclusive binding towards native gephyrin from brain lysates. We then designed and synthesized a series of dimeric ligands, which led to a remarkable 1220-fold enhancement of the gephyrin affinity (KD =6.8 nM). In X-ray crystal structures we visualized the simultaneous dimer-to-dimer binding in atomic detail, revealing compound-specific binding modes. Thus, we defined the molecular basis of the affinity-enhancing effect of multivalent gephyrin inhibitors and provide conceptually novel compounds with therapeutic potential, which will allow further elucidation of the gephyrin-receptor interplay.",
author = "Hans-Michael Maric and Kasaragod, {Vikram Babu} and Kedstr{\"o}m, {Linda Maria Haugaard} and Hausrat, {Torben Johann} and Matthias Kneussel and Hermann Schindelin and Kristian Str{\o}mgaard",
note = "{\circledC} 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",
year = "2015",
month = "1",
day = "7",
doi = "10.1002/anie.201409043",
language = "English",
volume = "54",
pages = "490--4",
journal = "Angewandte Chemie International Edition",
issn = "1433-7851",
publisher = "Wiley-VCH Verlag GmbH & Co. KGaA",
number = "2",

}

RIS

TY - JOUR

T1 - Design and Synthesis of High-Affinity Dimeric Inhibitors Targeting the Interactions between Gephyrin and Inhibitory Neurotransmitter Receptors

AU - Maric, Hans-Michael

AU - Kasaragod, Vikram Babu

AU - Kedström, Linda Maria Haugaard

AU - Hausrat, Torben Johann

AU - Kneussel, Matthias

AU - Schindelin, Hermann

AU - Strømgaard, Kristian

N1 - © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2015/1/7

Y1 - 2015/1/7

N2 - Gephyrin is the central scaffolding protein for inhibitory neurotransmitter receptors in the brain. Here we describe the development of dimeric peptides that inhibit the interaction between gephyrin and these receptors, a process which is fundamental to numerous synaptic functions and diseases of the brain. We first identified receptor-derived minimal gephyrin-binding peptides that displayed exclusive binding towards native gephyrin from brain lysates. We then designed and synthesized a series of dimeric ligands, which led to a remarkable 1220-fold enhancement of the gephyrin affinity (KD =6.8 nM). In X-ray crystal structures we visualized the simultaneous dimer-to-dimer binding in atomic detail, revealing compound-specific binding modes. Thus, we defined the molecular basis of the affinity-enhancing effect of multivalent gephyrin inhibitors and provide conceptually novel compounds with therapeutic potential, which will allow further elucidation of the gephyrin-receptor interplay.

AB - Gephyrin is the central scaffolding protein for inhibitory neurotransmitter receptors in the brain. Here we describe the development of dimeric peptides that inhibit the interaction between gephyrin and these receptors, a process which is fundamental to numerous synaptic functions and diseases of the brain. We first identified receptor-derived minimal gephyrin-binding peptides that displayed exclusive binding towards native gephyrin from brain lysates. We then designed and synthesized a series of dimeric ligands, which led to a remarkable 1220-fold enhancement of the gephyrin affinity (KD =6.8 nM). In X-ray crystal structures we visualized the simultaneous dimer-to-dimer binding in atomic detail, revealing compound-specific binding modes. Thus, we defined the molecular basis of the affinity-enhancing effect of multivalent gephyrin inhibitors and provide conceptually novel compounds with therapeutic potential, which will allow further elucidation of the gephyrin-receptor interplay.

U2 - 10.1002/anie.201409043

DO - 10.1002/anie.201409043

M3 - Journal article

C2 - 25413248

VL - 54

SP - 490

EP - 494

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

SN - 1433-7851

IS - 2

ER -

ID: 131462538