カテゴリー: Publication

【論文】渡邉くん, 田口くん, 竹尾さん, 飯尾くんの論文がChemical Communications にアクセプトされました!

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Strategic Alkene Incorporation into Peptide Backbones to Prevent Enzymatic Hydrolysis by Evading Molecular Recognition

Kohei Watanabe, Yoshinori Taguchi, Takuma Nishizawa, Sayuri Takeo, Chihiro Iio, Nobuyuki Mase, Kohei Sato*, Tetsuo Narumi*

This study highlighted a novel utility of alkene dipeptide isosteres  in peptide backbone modification, specifically at the C-terminal region of ubiquitin. By strategically replacing the Gly75-Gly76 peptide bond with these isosteres, we achieved significant resistance to a deubiquitinating enzyme, effectively preventing enzymatic hydrolysis while preserving the Gly76–Lys isopeptide bond targeted for hydrolysis. These findings demonstrate that strategic incorporation of these isosteres at key enzyme–substrate recognition sites substantially enhances peptide stability against enzymatic hydrolysis. This strategy offers a novel pathway for developing bioactive peptidomimetics and addresses longstanding limitations of conventional isostere applications by evading enzyme recognition.

Chem. Commun., accepted. 

 

【論文】竹尾さん, 竹田さん, 飯尾くん, 榊原さんの論文がJournal of Medicinal Chemistry にアクセプトされました! 北海道大学の渡邉先生や筑波大学の原田先生との共同研究成果です。

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Amide-to-Chloroalkene Substitution for Peptide Backbone Modification to Enhance Membrane Permeability

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.

J. Med. Chem. 2026, XX, XX.

【論文】今井くんの論文がResults in chemistry にアクセプトされました! 千葉大学の上原先生やQSTの樋口先生との共同研究成果です。

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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.

【論文】田口くん、西澤くんの論文がChemBioChemにアクセプトされました! 東京大学の佐伯先生との共同研究成果です。

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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.

【論文】近畿大学 伊藤先生、富山大学 髙﨑先生との共同研究がMed. Princ. Pract.にアクセプトされました。

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Long-lasting suppression of mechanical allodynia in mice by intrathecal administration of an anti-cell adhesion molecule 1 antibody

Ichiro Takasaki, Fuka Takeuchi, Ryohei Miyamae, Yuto Mochizuki, Hayate Kinoshita, Man Hagiyama, Azusa Yoneshige, Takao Inoue, Tetsuo Narumi, Akihiko Ito*

Med Princ Pract (2025) 34 (6): 614–623.

Objective: Cell adhesion molecule 1 (CADM1), an immunoglobulin superfamily member, is abundantly expressed on nerve fibers. Recently, the anti-CADM1 ectodomain antibody 3E1 has been shown to be potentially useful as a local anesthetic due to its high affinity for subcutaneous nerve fibers. When injected intrathecally into mice, where 3E1 accumulates, and whether it serves as an analgesic was examined.
Methods: The 3E1 injection was detected using indocyanine green-based imaging and immunohistochemistry. As a neuropathic pain model, mechanical allodynia-affected mice were created by spinal nerve ligation (SNL). These mice were administered intrathecally with 3E1, control antibody, or pregabalin, and then the pain threshold of the hind paw was measured using von Frey monofilaments. After SNL, followed by intrathecal injection of 3E1, real-time PCR was conducted to examine the expression of pain-related genes, interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor-α, chemokine (C-C motif) ligand (CCL) 2, CCL7, and CCL11.
Results: Intrathecally, injected 3E1 was localized mainly on the dorsal root ganglion cell bodies and spinal dorsal horn nerve fibers, with no motor side effects. In the von Frey test, 3E1-injected mice exhibited higher pain thresholds for up to 2 weeks compared to control mice. Pregabalin also raised the threshold, but the effect dissipated within 1 day. While SNL increased mRNA expression of all pain-related genes examined in spinal dorsal horn neurons, 3E1 injection suppressed the increased expression of IL-6.
Conclusion: 3E1 was suggested to be a potential ganglion-blocking analgesic and spinal anesthetic that acts ten or more times longer than pregabalin.

【論文】竹尾さん、沖田さんの論文がChem. Pharm. Bull.にアクセプトされました。静岡大学 大吉先生との共同研究の成果です。

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Identification of Guanine-Quadruplex-Binding Peptides from the RGG3 Domain of TLS/FUS

Sayuri Takeo, Maiko Tabata, Hikari Okita,  Natsuki Shibata, Kohei Sato, Nobuyuki Mase, Takanori Oyoshi,* and Tetsuo Narumi*

Chem. Pharm. Bull. 2025, 73, 938-943.

Guanine quadruplexes (G4s) are non-canonical nucleic acid structures that have emerged as attractive therapeutic targets owing to their involvement in diverse biological processes. Additionally, peptides derived from G4-binding proteins provide promising platforms for selective G4 recognition. In this study, we explored the G4-binding capacity of arginine-glycine-glycine (RGG)-rich sequences derived from the RGG3 domain of translocated in liposarcoma/fused in sarcoma (TLS/FUS), a known G4 RNA binding protein. In this study, we synthesized a library of overlapping 15-mer peptides and evaluated their G4-binding affinities. Among the 10 evaluated native sequences, several peptides demonstrated measurable affinities toward G4 RNA structures, with STK5-1 exhibiting the highest G4-binding affinity. Furthermore, to investigate the impact of conformational constraints on G4 recognition, we introduced (E)-methylalkene dipeptide isosteres (MADIs) into selected Gly–Gly motifs, generating a series of RGG peptidomimetics. Subsequent binding assays revealed that some of these MADI peptidomimetics exhibited enhanced affinity and selectivity compared with their unmodified counterparts. Our findings offer new insights into the sequence and structural features governing G4-binding, establishing a foundation for the further development of peptide-based G4 ligands.

【論文】川口くん、渡邉くん、田口くん、竹内くんの論文がJournal of Medicinal Chemistry (ACS Publications)にアクセプトされました。京都大学 尾勝先生・深井先生、東京大学 佐伯先生・冨田先生、鳥取大学・佐藤先生らとの共同研究の成果です。

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Adaptor-specific peptide inhibitors of the ubiquitin-chain-dependent unfolding activity of the human p97(VCP)–UFD1–NPL4 complex 

Kei Okatsu1, Takaya Kawaguchi, Kohei Watanabe, Yoshinori Taguchi, Reon Takeuchi, Akinori Okamoto, Yasuyuki Iwasa, Takuya Tomita, Yasushi Saeki, Yusuke Sato,* Tetsuo Narumi,* & Shuya Fukai*

J. Med. Chem., 2025, 68, 11270.

The AAA-ATPase p97, a key component of the ubiquitin-proteasome system (UPS), collaborates with its cofactor, the UFD1–NPL4 (UN) heterodimer, to unfold ubiquitinated substrates leading to proteasomal degradation. In this study, we report the development of novel peptide inhibitors that specifically target the p97–UN complex. These inhibitors are designed based on the NPL4-binding motif (NBM) of UFD1 and disrupt the interaction between p97 and the UN heterodimer. Our results demonstrate that these peptides effectively inhibit the unfolding activity of p97–UN, suggesting their potential as a therapeutic strategy for diseases associated with UPS dysfunction, such as cancer and neurodegenerative disorders. This work provides the first mechanistic insights into the inhibition of p97–UN by high-affinity peptide inhibitors and introduces promising candidates for drug development targeting the stable p97–UN complex in cells.

【論文】飯尾くんの論文がOrganic & Biomolecular Chemistry (Royal Society of Chemistry) にアクセプトされました。

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Racemization-free peptide bond formation via 2-nitrobenzensulfonyl strategy for diastereoselective synthesis of (Z)-fluoroalkene- type peptidomimetics

Chihiro Iio, Kohei Sato, Nobuyuki Mase, and Tetsuo Narumi*

Org. Biomol. Chem. 2025, 23, 4480.

The Xaa-Pro-type (Z)-fluoroalkene dipeptide isostere (FADI) serves as a versatile surrogate for peptide bonds, effectively restricting cis–trans isomerization of the prolyl amide bond and offering advantages in the development of conformationally constrained peptide analogues. However, the diastereoselective synthesis of tripeptidomimetics incorporating Xaa-Pro-type FADIs is challenging due to the high susceptibility to racemization of the α-stereogenic center during peptide bond formation. Here, we introduce a racemization- and epimerization-free coupling strategy for the stereoselective synthesis of fluoroalkene-type peptidomimetics by reacting Xaa-Pro-type FADIs with amino acid benzyl esters or peptides. This approach leverages the unique properties of the 2-nitrobenzenesulfonyl (Ns) group as an N-terminal protecting group, which promotes sulfonamide anion formation, effectively suppressing α-deprotonation and thereby preventing racemization or epimerization. Our findings highlight the pivotal role of the N-Ns group in peptide synthesis and provide a robust platform for expanding the utility of FADIs in peptidomimetic designing.

藤本さんが遷移状態計算した論文がOrganic Letters (ACS Publications)にアクセプトされました。北海道大学・渡邉先生・周東先生らとの共同研究の成果です。

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Highly Z-Selective Julia–Kocienski Olefination Using N-Sulfonylimines and Its Mechanistic Insights from DFT Calculations

Takuma Chizaki, Koichi Fujiwara, Junko Fujimoto, Tetsuo Narumi, Satoshi Shuto, and Mizuki Watanabe

Org. Lett. 2025, 27,  2677.

The Julia−Kocienski (JK) olefination is effective for E-selective olefination, but highly Z-selective versions remain rare. Here, we report a highly Z-selective JK olefination (Z ratio >99:1) using N-sulfonylimines as electrophiles instead of aldehydes. This method demonstrates a broad substrate scope, tolerating electron-donating and-withdrawing groups, amides, halogens, carboxylic acids, and hydroxyls. Z-selectivity in our system arises from both the 1,2-addition and Smiles rearrangement steps without involving synperiplanar elimination. This study expands the toolkit for Z-selective olefin synthesis.

竹尾さん、飯尾くん、榊原さん、竹田さんらの論文をChemRvixに公開しました。

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An amide-to-chloroalkene substitution improves the peptide permeability

Sayuri Takeo, Chihiro Iio, Ai Sakakibara, Mio Takeda, Yuki Yamazaki, Kohei Sato, Nobuyuki Mase, Mizuki Watanabe, Tetsuo Narumi

Chem Rxiv, 2024. DOI: 10.26434/chemrxiv-2024-l36zv

This study highlights the novel application of Chloroalkene Dipeptide Isosteres (CADIs) in enhancing peptide membrane permeability. Replacing the peptide bond with CADIs in model dipeptides significantly improved passive permeability. This enhancement is attributed to the increased lipophilicity provided by the CADI substitution, as confirmed by AlogP calculations and HPLC retention times. Molecular dynamics simulations further indicated that CADI substitution reduces water interaction, potentially lowering hydration energy. Our findings demonstrate that CADI incorporation can effectively improve the permeability of peptides, offering a valuable approach for developing bioactive peptidomimetics with enhanced pharmacological properties including permeability and hydrolytic stability.