Small Molecule Protein–Protein Interaction Inhibitors as CNS Therapeutic Agents: Current Progress and Future Hurdles

Blazer, Levi L.; Neubig, Richard R.

doi:10.1038/npp.2008.151

Cited by 163 publications

(153 citation statements)

References 156 publications

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“…This is particularly tempting for protein-protein interactions in the CNS where organization of larger multiprotein signaling complexes in distinct compartments is highly critical for neuronal function (7). Due to their key roles in the formation of these complexes, PDZ domains are predicted to be attractive targets because their well-defined binding crevices are likely to accommodate nonpeptide small-molecule ligands (6).…”

Section: Discussionmentioning

confidence: 99%

“…Efforts have consequently been directed toward identification of small-molecule nonpeptide PDZ domain inhibitors that could serve as leads in future drug discovery efforts (6,7). However, only a few compounds have been identified, and in general they display low affinities for their target (>100 μM) (10,11,(16)(17)(18).…”

mentioning

confidence: 99%

“…PSD-95/Discs-large/ZO-1 homology (PDZ) domains seem well suited for such efforts because they have a confined groove that typically binds the C-terminal three to four residues of the interaction partner (6) and thereby also are likely to accommodate nonpeptide small-molecule inhibitors (7). Additionally, PDZ domains are among the most common protein domains in the human genome serving important roles in protein trafficking as well as in the formation of multiprotein signaling complexes (6,8).…”

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confidence: 99%

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Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD

Thorsen

Madsen

Rebola

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

106

115

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Proteins containing PSD-95/Discs-large/ZO-1 homology (PDZ) domains play key roles in the assembly and regulation of cellular signaling pathways and represent putative targets for new pharmacotherapeutics. Here we describe the first small-molecule inhibitor (FSC231) of the PDZ domain in protein interacting with C kinase 1 (PICK1) identified by a screening of~44,000 compounds in a fluorescent polarization assay. The inhibitor bound the PICK1 PDZ domain with an affinity similar to that observed for endogenous peptide ligands (K i~1 0.1 μM). Mutational analysis, together with computational docking of the compound in simulations starting from the PDZ domain structure, identified the binding mode of FSC231. The specificity of FSC231 for the PICK1 PDZ domain was supported by the lack of binding to PDZ domains of postsynaptic density protein 95 (PSD-95) and glutamate receptor interacting protein 1 (GRIP1). Pretreatment of cultured hippocampal neurons with FSC231 inhibited coimmunopreciptation of the AMPA receptor GluR2 subunit with PICK1. In agreement with inhibiting the role of PICK1 in GluR2 trafficking, FSC231 accelerated recycling of pHluorin-tagged GluR2 in hippocampal neurons after internalization in response to NMDA receptor activation. FSC231 blocked the expression of both long-term depression and long-term potentiation in hippocampal CA1 neurons from acute slices, consistent with inhibition of the bidirectional function of PICK1 in synaptic plasticity. Given the proposed role of the PICK1/AMPA receptor interaction in neuropathic pain, excitotoxicity, and cocaine addiction, FSC231 might serve as a lead in the future development of new therapeutics against these conditions. drug discovery | fluorescence polarization | protein-protein interactions | synaptic plasticity | AMPA receptors

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD

Thorsen

Madsen

Rebola

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

106

115

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“…Given the very discrete protein expression pattern of RGS14 and the fact that RGS14-KO mice exhibit no obvious deleterious phenotypes, inhibition of RGS14 function may serve as an attractive therapeutic target for future cognitive enhancers (43,44).…”

Section: Discussionmentioning

confidence: 99%

RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory

Lee¹,

Simons

Heldt

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

176

337

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Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)-CA3-CA1 trisynaptic circuit of the hippocampus. Conspicuously absent from this circuit is area CA2, an intervening hippocampal region that is poorly understood. Schaffer collateral synapses on CA2 neurons are distinct from those on other hippocampal neurons in that they exhibit a perplexing lack of synaptic long-term potentiation (LTP). Here we demonstrate that the signaling protein RGS14 is highly enriched in CA2 pyramidal neurons and plays a role in suppression of both synaptic plasticity at these synapses and hippocampal-based learning and memory. RGS14 is a scaffolding protein that integrates G protein and H-Ras/ ERK/MAP kinase signaling pathways, thereby making it well positioned to suppress plasticity in CA2 neurons. Supporting this idea, deletion of exons 2-7 of the RGS14 gene yields mice that lack RGS14 (RGS14-KO) and now express robust LTP at glutamatergic synapses in CA2 neurons with no impact on synaptic plasticity in CA1 neurons. Treatment of RGS14-deficient CA2 neurons with a specific MEK inhibitor blocked this LTP, suggesting a role for ERK/MAP kinase signaling pathways in this process. When tested behaviorally, RGS14-KO mice exhibited marked enhancement in spatial learning and in object recognition memory compared with their wild-type littermates, but showed no differences in their performance on tests of nonhippocampal-dependent behaviors. These results demonstrate that RGS14 is a key regulator of signaling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory but distinct from the canonical DG-CA3-CA1 circuit.long-term potentiation | hippocampus | G protein signaling | RGS proteins | ERK

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“…The presence of PDZ proteins, such as the ones shown in Fig. 1A, in many important cellular processes, combined with the potential of PDZ proteins as therapeutic targets (Blazer and Neubig, 2009) justifies the significant and ongoing scientific interest in the PDZ domain.…”

Section: Introductionmentioning

confidence: 99%

Extensions of PDZ domains as important structural and functional elements

et al. 2010

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ABSTRACT'Divide and conquer' has been the guiding strategy for the study of protein structure and function. Proteins are divided into domains with each domain having a canonical structural definition depending on its type. In this review, we push forward with the interesting observation that many domains have regions outside of their canonical definition that affect their structure and function; we call these regions 'extensions'. We focus on the highly abundant PDZ (PSD-95, DLG1 and ZO-1) domain. Using bioinformatics, we find that many PDZ domains have potential extensions and we developed an openly-accessible website to display our results (http:// bcz102.ust.hk/pdzex/). We propose, using well-studied PDZ domains as illustrative examples, that the roles of PDZ extensions can be classified into at least four categories: 1) protein dynamics-based modulation of target binding affinity, 2) provision of binding sites for macro-molecular assembly, 3) structural integration of multi-domain modules, and 4) expansion of the target ligand-binding pocket. Our review highlights the potential structural and functional importance of domain extensions, highlighting the significance of looking beyond the canonical boundaries of protein domains in general.

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Small Molecule Protein–Protein Interaction Inhibitors as CNS Therapeutic Agents: Current Progress and Future Hurdles

Cited by 163 publications

References 156 publications

Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD

Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD

RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory

Extensions of PDZ domains as important structural and functional elements

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