Research ExplorerPublicationsDesign and synthesis of high-affinity dimeric inhibitors tar...

Design and synthesis of high-affinity dimeric inhibitors targeting the interactions between gephyrin and inhibitory neurotransmitter receptors

Standard

Design and synthesis of high-affinity dimeric inhibitors targeting the interactions between gephyrin and inhibitory neurotransmitter receptors. / Maric, Hans Michael; Kasaragod, Vikram Babu; Haugaard-Kedström, Linda; Hausrat, Torben Johann; Kneussel, Matthias; Schindelin, Hermann; Strømgaard, Kristian.

In: ANGEW CHEM INT EDIT, Vol. 54, No. 2, 07.01.2015, p. 490-4.

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

Harvard

Maric, HM, Kasaragod, VB, Haugaard-Kedström, L, 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', ANGEW CHEM INT EDIT, vol. 54, no. 2, pp. 490-4. https://doi.org/10.1002/anie.201409043

APA

Maric, H. M., Kasaragod, V. B., Haugaard-Kedström, L., 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. ANGEW CHEM INT EDIT, 54(2), 490-4. https://doi.org/10.1002/anie.201409043

Vancouver

Maric HM, Kasaragod VB, Haugaard-Kedström L, 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. ANGEW CHEM INT EDIT. 2015 Jan 7;54(2):490-4. https://doi.org/10.1002/anie.201409043

Bibtex

@article{22f25e522de94319bd3e0b24c320b12d,
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 = "Maric, {Hans Michael} and Kasaragod, {Vikram Babu} and Linda Haugaard-Kedstr{\"o}m and Hausrat, {Torben Johann} and Matthias Kneussel and Hermann Schindelin and Kristian Str{\o}mgaard",
note = "{\textcopyright} 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",
year = "2015",
month = jan,
day = "7",
doi = "10.1002/anie.201409043",
language = "English",
volume = "54",
pages = "490--4",
journal = "ANGEW CHEM INT EDIT",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",
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 - Haugaard-Kedström, Linda

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 - SCORING: Journal article

C2 - 25413248

VL - 54

SP - 490

EP - 494

JO - ANGEW CHEM INT EDIT

JF - ANGEW CHEM INT EDIT

SN - 1433-7851

IS - 2

ER -