Research
研究内容
The Sato Lab develops artificial molecules that mimic the structure and function of biomolecules in living organisms. The following is a brief summary of what we have developed to date.
佐藤研究室では，私たちの身体を構築している生体分子の構造や機能を模倣した人工分子の開発に挑んでいます。以下に，これまで報告してきた研究内容の一部をご紹介します。
1. Fluorinated Nanochannels (フッ素化人工チャネル)
The selective permeation of ions and water molecules across cellular membranes by channel proteins is a ubiquitous phenomenon observed in various aspects of biological events. Inspired by the structures and functions of such channel proteins, our group has developed a series of unique synthetic channels incorporating fluorine atoms, elements rarely found in natural proteins. We have demonstrated that fluorinated nanochannels exhibit anomalous material permeation properties, such as stimuli-responsive selective ion permeation and ultrafast selective water permeation.
私たちの身体を構成する細胞の表面には，特定の分子やイオンを通すチャネルタンパク質が存在しており，生命の維持に欠かせない役割を担っています。本研究では，このようなチャネルタンパク質の構造と機能からヒントを得つつも，天然のタンパク質にはほとんど存在しないフッ素原子を組み込んだ，ユニークな人工チャネルを開発しました。そして，天然の膜タンパク質を超えるほどの圧倒的なスピードで水を選択的に通す人工チャネルや，外部刺激に応答して特定のイオンを通す人工チャネルなどの開発に成功しています。
(1) Synthetic Ion Channel Formed by Multiblock Amphiphile with Anisotropic Dual Stimuli-Responsiveness
Ryo Sasaki, Kohei Sato*, Kazuhito Tabata, Hiroyuki Noji, Kazushi Kinbara*
J. Am. Chem. Soc. 2021, 143, 1348–1355.
(2) Ultrafast water permeation through nanochannels with a densely fluorous interior surface
Yoshimitsu Itoh*, Shuo Chen, Ryota Hirahara, Takeshi Konda, Tsubasa Aoki, Takumi Ueda, Ichio Shimada, James J. Cannon, Cheng Shao, Junichiro Shiomi, Kazuhito V. Tabata, Hiroyuki Noji, Kohei Sato*, Takuzo Aida*
Science 2022, 376, 738–743.
(3) Supramolecular Mechanosensitive Potassium Channel Formed by Fluorinated Amphiphilic Cyclophane
Kohei Sato*, Ryo Sasaki, Ryoto Matsuda, Mayuko Nakagawa, Toru Ekimoto, Tsutomu Yamane, Mitsunori Ikeguchi, Kazuhito V. Tabata, Hiroyuki Noji, Kazushi Kinbara*
J. Am. Chem. Soc. 2022, 144, 11802–11809.
2. Self-assembling peptides for regenerative medicine
(再生医療を志向した自己集合性ペプチド)
Fibrous extracellular matrices regulate cell growth and differentiation by interacting with cell receptors. In this study, we developed amphiphilic peptides that self-assemble into nanofibers and demonstrated their potential as regenerative medicines. Particularly, when the nanofibers were added to human iPS cell-derived neurons, the nanofibers showed significantly enhanced ability to promote neuronal cell growth compared to natural proteins with similar functions.
私たちの体内には細胞外マトリックスと呼ばれる，細胞の周囲を取り囲む繊維状の構造体が存在しており，細胞表面の受容体に作用することで細胞の成長や分化を制御しています。本研究では，このような細胞外マトリックスの構造と機能を模倣した自己集合性ペプチドを開発し，分子構造と生物活性との相関を明らかにしました。さらに，本研究で開発した自己集合性ペプチドをヒトiPS細胞由来神経に与えたところ，天然の同様の機能を有するタンパク質を上回るほどの神経細胞成長促進能を示すことが明らかとなりました。
(4) Programmable Assembly of Peptide Amphiphile via Noncovalent-to-Covalent Bond Conversion
Kohei Sato, Wei Ji, Liam C. Palmer, Benjamin Weber, Matthias Barz, Samuel I. Stupp*
J. Am. Chem. Soc. 2017, 139, 8995–9000.
(5) Chiral Recognition of Lipid Bilayer Membranes by Supramolecular Assemblies of Peptide Amphiphiles
Kohei Sato, Wei Ji, Zaida Àlvarez, Liam C. Palmer, Samuel I. Stupp*
ACS Biomater. Sci. Eng. 2019, 5, 2786–2792.
(6) Artificial extracellular matrix scaffolds of mobile molecules enhance maturation of human stem cell-derived neurons
Zaida Álvarez†, J Alberto Ortega†, Kohei Sato†, Ivan R Sasselli, Alexandra N Kolberg-Edelbrock, Ruomeng Qiu, Kelly A Marshall, Thao Phuong Nguyen, Cara S Smith, Katharina A Quinlan, Vasileios Papakis, Zois Syrgiannis, Nicholas A Sather, Chiara Musumeci, Elisabeth Engel, Samuel I Stupp*, Evangelos Kiskinis*
Cell Stem Cell 2023, 30, 219–238.
3. Understanding the mechanisms of refractory neurological diseases
(難治性神経疾患のメカニズム解明)
Amyotrophic lateral sclerosis (ALS) is an incurable neuronal disease that causes gradual loss of motor function throughout the body due to nerve degeneration. Recent studies have implicated dipeptide repeat proteins (DPRs) in the disease, but the basic physicochemical properties of DPRs remained largely unknown due to the difficulty of chemically synthesizing DPRs themselves. In this study, we succeeded in chemically synthesizing DPRs consisting of up to 200 amino acid residues using the automated fast-flow peptide synthesis, in which Fmoc-protected amino acids and coupling reagents are pumped at high temperature and high speed onto a peptide resin using a flow device. In addition, the physicochemical properties of the DPRs were elucidated, and the interaction between DPRs and RNA was found to be involved in the pathogenesis of ALS.
筋萎縮性側索硬化症（ALS）は神経の変性によって全身の運動機能が徐々に失われていく難治性疾患です。近年，ジペプチド・リピート（DPR）と呼ばれるタンパク質が疾患に関与していることが明らかになってきましたが，DPR自体の化学合成が困難であるために，その基本的な性質の大部分は未解明でした。本研究では，Fmoc 基で保護されたアミノ酸とカップリング剤をフロー装置によって高温・高速で固相担体へと送液し，担体上におけるカップリング反応の効率を著しく向上させる「固相フロー法」を用いることで，最長で200残基ものアミノ酸が連なったDPRを合成することに成功しました。さらに，得られたDPRの物理化学的性質を解明するとともに，ALSの発症にDPRとRNAとの相互作用が関与していることを明らかにしました。
(7) Automated Fast-Flow Synthesis of Chromosome 9 Open Reading Frame 72 Dipeptide Repeat Proteins
Kohei Sato, Charlotte E. Farquhar, Jacob Rodriguez, Bradley Pentelute*
J. Am. Chem. Soc. 2023, 145, 12992–12997.
Juan A. Ortega, Ivan R. Sasselli, Marco Boccitto, Andrew C. Fleming, Tyler R. Fortuna, Yichen Li, Kohei Sato, Tristan D. Clemons, Elizabeth D. Mckenna, Thao P. Nguyen, Eric N. Anderson, Jesus Asin, Justin K. Ichida, Udai B. Pandey, Sandra L. Wolin, Samuel I. Stupp, Evangelos Kiskinis*
Sci. Adv. 2023, 9, eadf7997.