Institute of Chemistry, Academia Sinica – Research
Directions
The research thrusts of the Institute are currently grouped along three major directions: materials chemistry, chemical synthesis and catalysis, and chemical biology. The current topics of materials sector include organic electroluminescent materials and devices, organic field-effect transistor materials and devices, photovoltaic materials and devices. The chemical catalysis and synthesis sector is focusing on the development of new synthetic methodology, drug discovery, carbohydrate chemistry, and the development of new catalytic systems for the generation of renewal energies and green fuels. The chemical biology program has made important advances in the delineation of bio-macromolecular structures and the development of new analytical platforms for disease detection and diagnosis.
Materials Chemistry: Organic Electronic and Optoelectronic Materialsy
Applications of organic optoelectronic materials and molecular engineering of nanomaterials are two major research directions under the materials division. Noticeable results include developments of blue fluorescent molecular materials for high performance organic light-emitting diodes, rational design of field-effective organic memory devices based on pentacene and gold nanoparticles, the very first stable organic thin film transistor based on single crystal of hexacene, rare single-walled metal–organic nanotube (MONT) with a large exterior wall diameter, the applications of metal-organic framework as optoelectronic materials, and a number of high performance materials for efficient solar energy harvesting devices such as dye-sensitized solar cells, perovskite solar cells, or organic photovoltaics. Researchers in this sector also develop stimuli-responsive materials, core-shell nanomaterials, and biomaterials. A recent report shows that a cell membrane–mimicking conducting polymer is capable to integrate biochemical and electrical stimulation to promote neural cellular behavior with great enhancement of neurite outgrowth on this conducting polymer.
Chemical Catalysis and Synthesis: Green Catalysis and Synthetic Methodology
In response to the increasingly demands of sustainable fuel and green synthetic technology, researchers in the organic synthesis and chemical catalysis divisions have strived to advance the development of cutting-edge technology for chemical transformations. The synthetic chemistry division of this sector focuses on the advances of synthetic methodology and drug discovery. The research topics under catalysis division is reconciling to catalysis relating to renewable energy. Major research directions in this sector include: (1) synthetic methodology: silyl ethers for hydroxy- directed nucleophilic acyl alkylation, microwave-assisted carbohydrate synthesis, smart fluorescent probes for bioorthogonal sugar labeling; (2) coordination chemistry: approaching unconventional catalysis via amino-NHC and carbodicarbene, unconventional porphyrin complexes for small molecule activations, engineering cytochrome P450 BM3 and alkane hydroxylase (AlkB) for alkane oxidations; (3) renewable energy catalysis: catalytic hydrogen evolution and mechanistic studies, encapsulated tricopper cluster for methane to methanol conversion, and novel catalysts for valorization of lignocellulosic biomass feedstocks.
Chemical Biology: New Material and Method towards Sustainable Health
Chemical biology division focus on the development of new material and methodology to explore the structure and function of macromolecules associated with cellular function or human diseases. The research activities are directed to unravel the underlying pathological mechanism and to derive new diagnostic and therapeutic strategies. Research topics in this division cover (1) development of smart biomaterials based on novel molecular principles; (2) chemical probe and advanced techniques in bio-imaging and structural biology; (3) drug discovery in cancer, infectious and neurodegenerative diseases; (4) development of structural biology techniques for infectious diseases, and (5) development of advanced proteomics strategies for biomarker discovery. The major achievements from the chemical biology group include the establishment of multiplexed quantitative strategy for membrane proteomics and post-translational modification for delineating disease mechanism and mining therapeutic targets discovery of amyloid fibrils induced from the TDP-43 in the Amyotrophic Lateral Sclerosis (ALS), and development of a photocontrollable probe to induce TDP-43 aggregates in live cells, mapping of the RNA exit channel on transcribing RNA polymerase II by FRET analysis, development of nano velcro chip to capture circulating tumor cells for liquid biopsy, construction of a near-infrared- activatable enzyme platform using an up-conversion nanoparticle to remotely trigger intracellular signal transduction.
利用蛋白水解靶向嵌合體(PROTACs)降解神經退化性疾病相關的TDP-43蛋白聚合物
Degradation of neurodegenerative disease-associated TDP-43 aggregates and oligomers via a proteolysis-targeting chimera
J. Biomed. Sci. 2023, 30, 27.
Yu-Ling Tseng, Po-Chao Lu, Chi-Chang Lee, Ruei-Yu He, Yung-An Huang, Yin-Chen Tseng, Ting-Jen Rachel Cheng, Joseph Jen-Tse Huang* & Jim-Min Fang*
近年來，與神經退化性疾病有關的錯誤摺疊蛋白，因為老化議題而受到廣泛的關注。在臨床上，可觀察到病人神經組織切片中錯誤摺疊蛋白有聚集的現象。然而，造成神經退化性疾病的聚集物一直以來都被認為是傳統抑制劑或拮抗劑無法針對的目標，因此，許多神經退化疾病的研究開始設計一些能夠清除錯誤摺疊蛋白聚集物的藥物(如清除 TDP-43 聚集物)。事實上，近年來 TDP-43 的聚集物也被視為判定肌萎縮性脊髓側索硬化症（ALS）與額顳葉失智症（FTLD）的指標蛋白。為了提供這樣的需求，我們與台灣大學化學系方俊民老師共同合作開發了一系列的蛋白水解靶向嵌合體（PROTACs）來清除 TDP-43 聚集物。在本篇研究中，我們利用在細胞中表達 TDP-43 聚集物的方式建立 PROTAC 化合物的篩選平台。透過這個平台，我們證明了 PROTAC 2 可與 TDP-43 聚集物結合。同時，我們也證實了 PROTAC 2 可以減少細胞中的 TDP-43 聚集物，以提高神經細胞的存活率。我們更透過了先進的顯微影像技術，進一步的證明 PROTAC 2 同時也降低了 TDP-43 寡聚體（oligomers）的數量。最後，我們觀察到 PROTAC 2 不僅可以減少線蟲（C. elegans）神經細胞中的 TDP-43 聚集物數量，也可以同時改善線蟲的運動能力。總括來說，我們的研究證明了新設計的 PROTAC 2 對於 TDP-43 聚集物與寡聚體具有雙重靶向能力，並增加細胞存活率，改善實驗動物的運動能力，為開發 ALS 以及其他神經退行性疾病的藥物提供了新的方向。
Amyotrophic lateral sclerosis (ALS) associated with TAR DNA-binding protein 43 (TDP-43) aggregation has been considered as a lethal and progressive motor neuron disease. Recent studies have shown that both C-terminal TDP-43 (C-TDP-43) aggregates and oligomers were neurotoxic and pathologic agents in ALS and frontotemporal lobar degeneration (FTLD). However, misfolding protein has long been considered as an undruggable target by applying conventional inhibitors, agonists, or antagonists. To provide this unmet medical need, we aim to degrade these misfolding proteins by designing a series of proteolysis targeting chimeras (PROTACs) against C-TDP-43. We showed that PROTAC 2 bound to C-TDP-43 aggregates and E3 ligase to initiate ubiquitination and proteolytic degradation. By applying advanced microscopy, it was further shown that PROTAC 2 decreased the compactness and population of C-TDP-43 oligomers. In addition to cellular model, PROTAC 2 also improved the motility of transgenic C. elegans by reducing the C-TDP-43 aggregates in the nervous system. Our study demonstrated the dual-targeting capacity of the newly-designed PROTAC 2 against both C-TDP-43 aggregates and oligomers to reduce their neurotoxicity, which shed light on the potential drug development for ALS as well as other neurodegenerative diseases.