Design and Synthesis of Highly Potent and Plasma-Stable Dimeric Inhibitors of the PSD-95-NMDA Receptor Interaction

被引：53

作者：

Bach, Anders ^{[1
]}

Chi, Celestine N. ^{[2
]}

Pang, Gar F. ^{[1
]}

Olsen, Lars ^{[1
]}

Kristensen, Anders S. ^{[1
]}

Jemth, Per ^{[2
]}

Stromgaard, Kristian ^{[1
]}

机构：

[1] Univ Copenhagen, Dept Med Chem, DK-2100 Copenhagen, Denmark

[2] Uppsala Univ, Dept Med Biochem & Microbiol, S-75123 Uppsala, Sweden

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2009年 / 48卷 / 51期

基金：

瑞典研究理事会;

关键词：

bridging ligands; dimerization; inhibitors; protein-protein interactions; receptors; PDZ DOMAIN PROTEINS; FLEXIBLE LINKERS; BINDING; LIGAND; AFFINITY; ANTAGONISTS; PEPTIDES; TARGETS; STROKE;

D O I：

10.1002/anie.200904741

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

On the double: Dimerization of monomeric peptide ligands towards the PDZ domains of the protein PSD-95 (postsynaptic density 95) leads to potent inhibitors of protein-protein interactions with stability in blood plasma. Optimization of the length of the polyethylene glycol linker results in unprecedented affinity for inhibitors of the PDZ1-2 domain (see picture). © 2009 Wiley-VCH Verlag GmbH &. Co. KGaA.

引用

页码：9685 / 9689

页数：5

共 32 条

[1] Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions [J].

Aarts, M ;

Liu, YT ;

Liu, LD ;

Besshoh, S ;

Arundine, M ;

Gurd, JW ;

Wang, YT ;

Salter, MW ;

Tymianski, M .

SCIENCE, 2002, 298 (5594) :846-850

[2] Modified Peptides as Potent Inhibitors of the Postsynaptic Density-95/N-Methyl-D-Aspartate Receptor Interaction [J].

Bach, Anders ;

Chi, Celestine N. ;

Olsen, Thomas B. ;

Pedersen, Soren W. ;

Roder, Martin U. ;

Pang, Gar F. ;

Clausen, Rasmus P. ;

Jemth, Per ;

Stromgaard, Kristian .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (20) :6450-6459

[3] Small Molecule Protein-Protein Interaction Inhibitors as CNS Therapeutic Agents: Current Progress and Future Hurdles [J].

Blazer, Levi L. ;

Neubig, Richard R. .

NEUROPSYCHOPHARMACOLOGY, 2009, 34 (01) :126-141

[4] Making protein interactions druggable: Targeting PDZ domains [J].

Dev, KK .

NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (12) :1047-1056

[5]

Dingledine R, 1999, PHARMACOL REV, V51, P7

[6] Organization and dynamics of PDZ-domain-related supramodules in the postsynaptic density [J].

Feng, Wei ;

Zhang, Mingjie .

NATURE REVIEWS NEUROSCIENCE, 2009, 10 (02) :87-99

[7] New targets for pharmacological intervention in the glutamatergic synapse [J].

Gardoni, Fabrizio ;

Di Luca, Monica .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2006, 545 (01) :2-10

[8] The kinetics of PDZ domain-ligand interactions and implications for the binding mechanism [J].

Gianni, S ;

Engström, Å ;

Larsson, M ;

Calosci, N ;

Malatesta, F ;

Eklund, L ;

Ngang, CC ;

Travaglini-Allocatelli, C ;

Jemth, P .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (41) :34805-34812

[9] Pegylation - A novel process for modifying pharmacokinetics [J].

Harris, JM ;

Martin, NE ;

Modi, M .

CLINICAL PHARMACOKINETICS, 2001, 40 (07) :539-551

[10] The rise and fall of NMDA antagonists for ischemic. stroke [J].

Hoyte, L ;

Barber, PA ;

Buchan, AM ;

Hill, MD .

CURRENT MOLECULAR MEDICINE, 2004, 4 (02) :131-136

← 1 2 3 4 →