Organic Chemistry for Drug Discovery
2026年3月、日本薬学会 第146回にて、当研究室の大学生2名、大学院生1名が発表しました。
M1 豊田 剛亮
28-64-pm2-30S『核内受容体Nr4a1を標的としたジヒドロキナゾリノン誘導体の構造最適化研究』
B4 片岡伸太郎
27-61-pm2-36S『オクトレオチドの配座制御を指向したTrp-Lys型クロロアルケンジペプチ
ドイソスターの合成研究』
B4 花村継
27-61-pm1-19s『(E)-メチルアルケン型ペプチド結合等価体を導入したプロリンエステルミミックの合成と配座解析』
多くの皆様にディスカッションいただき、今後の展開に向けた貴重なフィードバックを得ることができました。心より感謝申し上げます！
ペプチド結合等価体であるクロロアルケンジペプチドイソスターがペプチドの細胞膜透過性を向上させることを明らかにした共同研究が、Journal of Medicinal Chemistry に掲載されました。本研究成果は現在本学HPにてプレスリリースされています。
論文タイトル：Amide-to-Chloroalkene Substitution for Peptide Backbone Modification to Enhance Membrane Permeability
著者名：Sayuri Takeo, Mio Takeda, Chihiro Iio, Ai Sakakibara, Showmitra Saha, Natsuki Shibata, Yuki Yamazaki, Takahiro Fujii, Ryuhei Harada, Kohei Sato, Nobuyuki Mase, Mizuki Watanabe, Takanori Oyoshi* and Tetsuo Narumi*
掲載誌：Journal of Medicinal Chemistry
掲載日：2026年2月20日
DOI：10.1021/acs.jmedchem.5c02090
Sayuri Takeo, Mio Takeda, Chihiro Iio, Ai Sakakibara, Showmitra Saha, Natsuki Shibata, Yuki Yamazaki, Takahiro Fujii, Ryuhei Harada, Kohei Sato, Nobuyuki Mase, Mizuki Watanabe, Takanori Oyoshi*, Tetsuo Narumi*
Herein, we report a systematic evaluation of backbone modification strategies to enhance peptide membrane permeability, focusing on chloroalkene dipeptide isosteres (CADIs) as amide bond surrogates. A direct comparison with classical modifications─including N-methylation, esterification, and thioamidation─reveals that CADI substitution consistently provides the highest improvement in both passive diffusion and cellular uptake. Mechanistic analyses combining A log P calculations, HPLC profiling, and molecular dynamics simulations attribute this effect primarily to improved lipophilicity and reduced hydration, rather than conformational changes. Notably, CADI substitution is successfully extended to longer polar sequences and cyclic scaffolds, and it preserves or enhances RNA-binding affinity and selectivity in G-quadruplex-binding RGG peptides. Overall, this study establishes CADI substitution as a robust backbone modification strategy that enables the design of peptidomimetics with enhanced membrane permeability and improved resistance to hydrolytic stability.
Development of a Novel Methylated PET Tracer Designed to Enhance the Photostability of PM-PBB3
Tomoyuki Imai, Yuta Tanaka, Kento Kannaka, Hiroyuki Suzuki, Masayuki Fujinaga, Hiroshi Mizuma, Ming-Rong Zhang, Makoto Higuchi, Tetsuo Narumi, Tomoya Uehara
Results in Chemistry 2026, 20, 102979.
Molecular imaging of tau protein accumulation plays a vital role in elucidating the pathology and enabling early diagnosis of tauopathies, including Alzheimer’s disease (AD). [18F]PM-PBB3 is a promising tau positron emission computed tomography (PET) tracer with high selectivity and affinity for tau lesions in both AD and non-AD tauopathies. However, its clinical application is hindered by poor photostability owing to rapid photoisomerization. In this study, we synthesized a novel derivative of PM-PBB3, Me-PM-PBB3, by introducing a methyl group at the γ-position of the former to improve photostability. Compared to PM-PBB3, Me-PM-PBB3 showed a blue-shifted absorption maximum and lower molar extinction coefficient, resulting in a more than 100-fold increase in resistance to photodegradation. Fluorescence staining of AD brain sections demonstrated that Me-PM-PBB3 bound to neurofibrillary tangles. PET imaging using rTg4510 mice, a tauopathy model, revealed that [18F]Me-PM-PBB3 accumulates in the cortex and hippocampus, indicating its effectiveness as a tau PET tracer. However, increased non-specific binding in white matter was also observed, suggesting that structural modifications may affect its in vivo kinetics. Overall, this study presents a novel chemical approach to enhance the photostability of tau PET tracers and suggests Me-PM-PBB3 as a promising candidate for future applications in the diagnosis of tau-related neurodegenerative diseases.
A Stable Bioisostere of Ester-Linked Ubiquitin Chains Enables Decoding of Protein Interactors
Yoshinori Taguchi,† Takuya Tomita,† Takuma Nishizawa, Dai Nakamura, Showmitra Saha, Takanori Oyoshi, Kohei Sato, Nobuyuki Mase, Yasushi Saeki, and Tetsuo Narumi (†: These authors contributed equally to this work)
ChemBioChem 2026, 27, e202500749.
Protein ubiquitination is a pivotal post-translational modification that regulates diverse biological processes depending on the type of ubiquitin chain linkage. Recently, ester-linked ubiquitin chains have been identified, yet their inherent hydrolytic instability has posed a significant challenge for biochemical investigations. In this study, we chemically synthesized a stable and isosteric amide analog of an ester-linked ubiquitin dimer, in which serine (Ser) at position 20 of the proximal ubiquitin was replaced with 2,3-diaminopropionic acid (Dap). The desired amide analog was synthesized using a convergent approach involving the sequential chemoselective ligation of three peptide fragments generated through Fmoc-based solid-phase peptide synthesis. Employing this chemically robust ubiquitin probe, we uncovered a previously unrecognized interaction between Ser20- linked ubiquitin chains and spliceosome-associated factors, notably ubiquitin-specific protease 39 (USP39). These findings highlight the potential of our ester-to-amide bioisosteric strategy to unlock mechanistic insights into atypical ubiquitin modifications. Our approach not only circumvents the intrinsic instability of ester-linked ubiquitin chains but also provides a broadly applicable framework for dissecting their biological roles, paving the way for future discoveries in ubiquitin signaling.
2025年11月、第51回反応と合成の進歩シンポジウム にて、当研究室の大学院生1名が発表しました。
D3 田口佳紀
ポスター番号: 2P-20
「エステル連結ユビキチン鎖の機能解明を指向したアミド型アナログの創製」
多くの皆様にディスカッションいただき、今後の展開に向けた貴重なフィードバックを得ることができました。心より感謝申し上げます！
当研究室の博士後期課程2年・飯尾智裕くんが、（International Conference on Green Science and Technology 2025 (ICGST-2025にて、学生優秀発表賞を受賞しました！
発表タイトルは、
「Conformationally Constrained Peptidomimetics via Fluoroalkene Incorporation: From Synthesis to Tau Aggregation Control」。
ペプチド主鎖改変によるアミド配座の固定化を創薬展開した先進的な研究内容が高く評価されました。飯尾くん、受賞おめでとうございます！
2025年11月、第42回メディシナルケミストリーシンポジウム (MCS)にて、当研究室の大学院生5名が発表しました。
D1 岸川聖
2P-07「Struature-Activity Relationship Study of Tetrahydrocarbazole Derivatives Inhibiting HCV Particle Formation」
M2 竹田実央
2P-028「Development of Chloroalkene-type hNMUR2-Selective Peptide Agonists for Overcoming Intramolecular Acyl Transfer」
M2 宮田陽伊
2P-29「Development of CADI-ααAA Hybrid-type Somatostatin Analogue for Peptide Structure Control」
M1 竹田和真
2P-30「Development of Peptidic HBV Capsid Assembly Inhibitors Derived from HBV Core Protein」
D3 竹尾沙優里
2P-32「Amide-to-Chloroalkene Substitution for Peptide Backbone Modification to Enhance Membrane Permeability」
多くの皆様にディスカッションいただき、今後の展開に向けた貴重なフィードバックを得ることができました。心より感謝申し上げます！
2025年11月、International Conference on Green Science and Technology 2025 (ICGST-2025) にて、当研究室の大学院生1名が発表しました。
D2 飯尾 智裕
「Conformationally Constrained Peptidomimetics via Fluoroalkene Incorporation: From Synthesis to Tau Aggregation Control」
多くの皆様にディスカッションいただき、今後の展開に向けた貴重なフィードバックを得ることができました。心より感謝申し上げます！
当研究室の博士後期課程2年・飯尾智裕くんが、第62回 ペプチド討論会（2025年開催）にて、学生優秀発表賞を受賞しました！
発表タイトルは、
「Fluoroalkene dipeptide isosteres in tau-derived peptides elucidate the role of prolyl amide isomerization in tau aggregation」。
ペプチド主鎖改変によるアミド配座の固定化を創薬展開した先進的な研究内容が高く評価されました。飯尾くん、受賞おめでとうございます！
