57 research outputs found
PROTACs and Other Chemical Protein Degradation Technologies for the Treatment of Neurodegenerative Disorders
No full text学術論文(Ariticle)journal articl
標的タンパク質のリガンドを必要としないプロテインノックダウン法
No full text学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 橋本 祐一, 東京大学教授 井上 将行, 東京大学教授 船津 高志, 東京大学教授 富田 泰輔, 東京大学准教授 花岡 健二郎University of Tokyo(東京大学
Total Syntheses of Pyocyanin, Lavanducyanin, and Marinocyanins A and B
No full textTotal syntheses of
pyocyanin, lavanducyanin, and marinocyanins
A and B have been accomplished. The N-substituted
phenazin-1-one skeleton, a common framework of these natural products,
was constructed through the oxidative condensation of pyrogallol with N-substituted benzene-1,2-diamine under an oxygen atmosphere
in a single step. Regioselective bromination with N-bromosuccinimide at the C-2 position of N-alkylated
phenazin-1-ones afforded brominated natural products
Targeted Protein Degradation in the Mitochondrial Matrix and Its Application to Chemical Control of Mitochondrial Morphology
No full textDysfunction of mitochondria is implicated in various diseases, including cancer and neurodegenerative disorders, but drug discovery targeting mitochondria and mitochondrial proteins has so far made limited progress. Targeted protein degradation (TPD) technologies represented by proteolysis targeting chimeras (PROTACs) are potentially applicable for this purpose, but most existing TPD approaches leverage the ubiquitin-proteasome system or lysosomes, which are absent in mitochondria, and TPD in mitochondria (mitoTPD) remains little explored. Herein, we describe the design and synthesis of a bifunctional molecule comprising TR79, an activator of the mitochondrial protease complex caseinolytic protease P (ClpP), linked to desthiobiotin. This compound successfully induced the degradation of monomeric streptavidin (mSA) and its fusion proteins localized to the mitochondrial matrix. Furthermore, in cells overexpressing mSA fused to short transmembrane protein 1 (mSA-STMP1), which enhances mitochondrial fission, our mitochondrial mSA degrader restored the mitochondrial morphology by reducing the level of mSA-STMP1. A preliminary structure-activity relationship study indicated that a longer linker length enhances the degradation activity towards mSA. These findings highlight the potential of mitoTPD as a tool for drug discovery targeting mitochondria and for research in mitochondrial biology, as well as the utility of mSA as a degradation tag for mitochondrial protein
Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole derivative
No full textSelective Degradation of Target Proteins by Chimeric Small-Molecular Drugs, PROTACs and SNIPERs
No full textNew therapeutic modalities are needed to address the problem of pathological but undruggable proteins. One possible approach is the induction of protein degradation by chimeric drugs composed of a ubiquitin ligase (E3) ligand coupled to a ligand for the target protein. This article reviews chimeric drugs that decrease the level of specific proteins such as proteolysis targeting chimeric molecules (PROTACs) and specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), which target proteins for proteasome-mediated degradation. We cover strategies for increasing the degradation activity induced by small molecules, and their scope for application to undruggable proteins
Analytical regularization of hypersingular integral for Helmholtz equation in boundary element method
No full textThis paper presents a gradient field representation using an analytical regularization of a hypersingular boundary integral equation for a 2-dimensional time harmonic wave equation called the Helmholtz equation. The regularization is based on cancelation of the hyper-singularity by considering properties of hypersingular elements that are adjacent to a singular node. Advantages to this regularization include applicability to evaluate cornet nodes, no limitation for element size, and reduced computational cost compared to other methods. To demonstrate capability and accuracy, regularization is estimated for a problem about plane wave propagation. As a result, it is found that even at a corner node the most significant error in the proposed method is due to truncation error of non-singular elements in discretization, and error from hypersingular elements is negligibly small
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