Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1039/d1cb00195g

Web of Science

Language：English   Publisher：Frontiers in Chemistry  

Cell-surface receptors play a pivotal role as transducers of extracellular input. Although different cell types express the same receptor, the physiological roles of the receptor are highly dependent on cell type. To understand each role, tactics for cell-specific activation of the target receptor are in high demand. Herein, we developed an orthogonal activation method targeting metabotropic glutamate receptor 1 (mGlu1), a G-protein coupled receptor. In this method, direct activation via coordination-based chemogenetics (dA-CBC) was adopted, where activation of mGlu1 was artificially induced by a protein conformational change in response to the coordination of a metal ion or metal-ion complex. Our structure-based protein design and screening approach identified mGlu1 mutants that were directly activated by the coordination of Cu2+ or Zn2+, in addition to our previous Pd-complex-sensitive mGlu1 mutant. Notably, the activation of the mutants was mutually orthogonal, resulting in cell-type selective activation in a model system using HEK293 cells.

DOI： 10.3389/fchem.2021.825669

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

<p>Approaches for selective and rapid modulation are ideal for investigating the physiological roles of proteins. This review focuses on chemogenetic approaches in which designer molecules are attached to the target protein for the modulation of proteins in live cells.</p>

DOI： 10.1039/d1cs00059d

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>The regulation of glutamate receptor localization is critical for development and synaptic plasticity in the central nervous system. Conventional biochemical and molecular biological approaches have been widely used to analyze glutamate receptor trafficking, especially for α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate-type glutamate receptors (AMPARs). However, conflicting findings have been reported because of a lack of useful tools for analyzing endogenous AMPARs. Here, we develop a method for the rapid and selective labeling of AMPARs with chemical probes, by combining affinity-based protein labeling and bioorthogonal click chemistry under physiological temperature in culture medium. This method allows us to quantify AMPAR distribution and trafficking, which reveals some unique features of AMPARs, such as a long lifetime and a rapid recycling in neurons. This method is also successfully expanded to selectively label <italic>N</italic>-methyl-D-aspartate-type glutamate receptors. Thus, bioorthogonal two-step labeling may be a versatile tool for investigating the physiological and pathophysiological roles of glutamate receptors in neurons.

DOI： 10.1038/s41467-021-21082-x

Web of Science

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PubMed

Other Link： http://www.nature.com/articles/s41467-021-21082-x

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Bioorganic and Medicinal Chemistry Letters  

Dantrolene, the only therapeutic agent for malignant hyperthermia, is known to have not only a muscle relaxant effect, but also a neuroprotective effect and Alzheimer's disease improving effect. Recently, it has been reported that dantrolene has a weak inhibitory effect on acetylcholinesterase (AChE), which is a therapeutic drug target for Alzheimer's disease. Thus, we focused on developing of AChE inhibitors with benzylpiperidine/piperazine moieties that are based on the dantrolene skeleton. Several derivatives showed an inhibitory activity. Among them, ortho-nitro derivative 8c showed the most potent inhibitory activity with the IC50 value of 34.2 nM. Furthermore, Lineweaver-Burk plot analysis indicated that 8c is AChE-selective inhibitor, which shows only a weak inhibitory effect on butyrylcholinesterase (BuChE) and a non-competitive inhibition.

DOI： 10.1016/j.bmcl.2019.126888

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Part of collection (book)   Publisher：公益社団法人 日本薬学会  

生体中には800種類以上のGタンパク質共役型受容体(GPCRs)が存在している．個々のGPCRの生物学的・病理学的機能を解明することは生命機能や病態の理解，治療法の開発に結びつくため重要である．代表的なGPCRの化学遺伝学的活性制御法はdesigner receptors exclusively activated by designer drugs(DREADDs)であるが，本手法で使用されるムスカリン受容体は人工リガンドにのみ結合するように改変されているため，本来の機能を喪失している．<br>そこで，標的GPCRの機能を維持したままGPCRの機能を解明する化学遺伝学的手法として，Broichhagen J.らは光刺激によってGPCRの活性を制御するphotoswitchable orthogonal remotely tethered ligand(PORTL)を開発した．細胞表層にSNAP-tag融合代謝型グルタミン酸受容体2(SNAP-mGluR2)を発現させ，mGluR2の天然アゴニストであるグルタミン酸・光スイッチ部位・SNAP-tag基質を適切なリンカーで連結した分子(BGAG)でラベル化して作製したPORTL(SNAG-mGluR2)に光照射することによりSNAG-mGluR2の活性制御に成功している．しかし，PORTLは原理的に内在性GPCRの活性を制御できない．<br>本稿では， Donthamsetti P. C.らが開発した内在性GPCRの活性を光制御可能なPORTLの発展型であるmaPORTLについて紹介する．<br>なお，本稿は下記の文献に基づいて，その研究成果を紹介するものである.<br>1) Urban D. J. <i>et</i> <i>al</i>., <i>Annu</i>. <i>Rev</i>. <i>Pharmacol</i>. <i>Toxicol</i>., <b>55</b>, 399-417(2015)．<br>2) Broichhagen J. <i>et</i> <i>al</i>., <i>ACS</i> <i>Cent</i>. <i>Sci</i>., <b>1</b>, 383-393(2015)．<br>3) Donthamsetti P. C. <i>et</i> <i>al</i>., <i>J</i>. <i>Am</i>. <i>Chem</i>. <i>Soc</i>., <b>141</b>, 11522-11530(2019)．

DOI： 10.14894/faruawpsj.56.5_441

CiNii Research

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Academic Press Inc.  

Thiol-organosilica nanoparticles are a promising nanomaterial for biomedical applications. The enhanced permeability and retention (EPR) effect is useful for tumor targeting within the biomedical applications of nanomaterials, and nanomaterials with a size of less than 200 nm exhibit the maximum EPR effect. However, the synthesis of thiol-organosilica nanoparticles with a diameter of less than 200 nm is not efficient for the yield using the present conventional synthetic methods. Herein, we report the development of an efficient synthetic method of thiol-organosilica nanoparticles with a diameter of less than 200 nm using an anionic surfactant and discuss its mechanism. Compared with the conventional synthetic methods, a greater than 10-fold miniaturization of thiol-organosilica nanoparticles and an approximately 40-fold increase in the production efficiency of small thiol-organosilica nanoparticles were achieved using the sodium dodecyl sulfate (SDS)-addition synthetic method or sodium dodecylbenzenesulfonate (SDBS)-addition synthetic method. This is the first report about the miniaturization of organosilica nanoparticles induced by an anionic surfactant. The SDS-addition synthetic method or SDBS-addition synthetic method will accelerate the biomedical applications of thiol-organosilica nanoparticles.

DOI： 10.1016/j.jcis.2018.04.090

Scopus

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)