Cell-penetrating peptides (CPPs) hold great potential as tools for drug delivery systems (DDSs). Numerous research groups have developed novel CPPs with enhanced functionality and safety. This review highlights recent advancements in CPP research by my research group and our collaborators. We have designed novel CPPs incorporating unnatural amino acids, explored their applications in DDSs, and elucidated their functional mechanisms.

This review summarizes the structures, names, and bioactivities of 207 briarane-type diterpenoids, including 113 newly identified metabolites, isolated between 2020 and 2024. All the briaranes discussed were derived from octocorals belonging to the genera Briareum, Dichotella, Ellisella, Junceella, and Erythropodium. Some of these compounds have demonstrated potential biomedical activities.

Unprotected amino acids are completely insoluble in organic solvents, limiting their use in organic synthesis. To address this issue, we report a Ta-catalyzed strategy for the elongation of unprotected amino acids using N-trimethylsilylimidazole. More specifically, silylation of the unprotected amino acids was carried out at both termini to generate a linear intermediate that was soluble in organic solvents, thereby permitting the efficient introduction of amino acid esters at the C-terminus. Furthermore, the in situ silicon protection approach employed herein was applicable to varying lengths of amino acid chains, leading to the generation of N-unprotected β-, γ-, and δ-peptides without any loss of enantio- or diastereopurity. These innovative results have facilitated the elimination of several steps in the preparation of desired peptides and have simplified the synthesis of peptides containing long-chain amino acids and branched peptides.

Exposures to ionizing radiation can cause serious damages to human body, and the development of radiation countermeasures is urgently needed. In this paper, a series of N-phenyl-2H-chromene-3-carboxamides were designed and synthesized as potential radiation countermeasures. Their radioprotective activities were evaluated in vitro and in vivo, and compound B5 was identified as the most effective molecule among the target compounds. B5 can not only accelerate the recovery of peripheral blood cells in mice exposed to total body irradiation, but also alleviate damage to the small intestine, spleen and thymus in mice exposed to abdominal irradiation. Furthermore, B5 exhibited superior ability to mitigate radiation-induced DNA damage and apoptosis in irradiated AHH-1 cells. Western blot analysis indicated that the radioprotection provided by B5 resulted in the downregulation of pro-apoptosis proteins p53 and upregulation of anti-apoptosis protein Bcl-2. In addition, the RNA-Sequencing analysis revealed that B5 primarily exerts its radioprotective effects through the Wnt signaling pathway and the mitogen-activated protein kinase (MAPK) signaling pathway. In conclusion, we identified B5 as a promising radioprotective compound, and B5 is valuable for further research in the future.

Newly designed optically active cage type 2-azanorbornane-based amino amide organocatalysts were developed and employed in the asymmetric Michael addition of β-keto esters with nitroolefins to afford the chiral Michael adducts with good chemical yields (up to 99%) and stereoselectivities (up to diastereomeric ratio (dr) = 97 : 3, up to 96% enantiomeric excess (ee)).

Ephedrine alkaloids-free Ephedra Herb extract (EFE) and its component, Ephedra Herb macromolecule condensed-tannin (EMCT), have been shown to exhibit anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity in VeroE6/TMPRSS2 cells. Therefore, it is expected that EFE will be developed as a new natural product drug that exhibits anti-SARS-CoV-2 effects. In this study, we analyzed the molecular mechanism of EMCT’s anti-SARS-CoV-2 activity, namely, inhibition of the binding of the viral spike (S) protein to angiotensin-converting enzyme 2 (ACE2), to confirm that EMCT is an active component of the anti-SARS-CoV-2 effect. Furthermore, matrix-assisted laser desorption/ionization time-of-flight-MS of EMCT was performed to determine its molecular mass distribution, resulting in a mass spectrum that exhibited a broad single peak at approximately 60000 and a mass range of m/z 30000–120000. In a binding assay of the receptor-binding domain of the S protein to ACE2, EMCT inhibited this interaction with an IC₅₀ of 48 nM. According to surface plasmon resonance analysis, EMCT binds to both the S protein and ACE2 with K_D values of 39 and 44 nM, respectively. Furthermore, the interaction between the predicted substructure of EMCT, flavan-3-ol tetramers, and the S protein was evaluated in silico, indicating that the possible binding site is the ACE2-binding region of the S protein. These results suggest that the anti-SARS-CoV-2 activity of EMCT is exerted through inhibition of S protein/ACE2-mediated viral infection. Therefore, EMCT is thought to be the most useful ingredient for quality control of EFE as an investigational extract drug.

Iodine L-edge X-ray absorption near-edge structure (XANES) measurements were performed to characterize each crystal form of the compounds containing iodine atoms. 4-Iode-l-phenylalanine (4ILP) was used as a model compound. Each crystalline form had a distinctive XANES spectral shape. Complementary single-crystal X-ray structure analyses revealed diverse atomic interactions surrounding the iodine atoms, including C···I contacts and I···I halogen bonds. These different interactions influence the electronic states of the iodine atoms of 4ILP, resulting in distinct features in the XANES spectra. Notably, the spectral changes in the L₁ absorption edge of iodine atoms were found to be sensitive to van der Waals contacts. On the other hand, those in L₂ and L₃ were sensitive to the presence or absence of halogen bonds. This research highlights the crucial impact of weak nonconventional atomic interactions on the XANES spectra, providing valuable insights for the development and evaluation of crystalline materials.

Glycans, as one of the fundamental biomolecules alongside nucleic acids and proteins, play critical roles in biological processes, including glycoprotein folding, transport, degradation, and cell–cell interactions. Despite their biological importance, the structural analysis of glycans remains challenging due to their high flexibility and complex branched structures. This study addresses these challenges by combining molecular dynamics (MD) simulations and NMR spectroscopy to obtain dynamic conformational ensembles of glycans. Nonlinear correlation analyses, specifically Hilbert–Schmidt independence criterion and maximal information coefficient, were applied to decipher the structural dynamics of glycans. The study focused on GM3 trisaccharides and high-mannose glycans (GM9, M9, and M8B), uncovering the roles of glycosidic dihedral angles and intramolecular hydrogen bonds in stabilizing specific conformations. Key correlations between glycosidic linkages and hydrogen bonds were identified, offering insights into the conformational changes that underpin glycan bioactivity. Notably, the removal of specific mannose residues disrupts hydrogen bond networks, expanding conformational space and influencing glycoprotein fate in the endoplasmic reticulum. By integrating MD simulations, NMR validation, and nonlinear multivariate analysis, this study provides a robust framework for understanding glycan structural dynamics. These findings have broad implications for glycoengineering, glycan-based drug discovery, and the design of therapeutics targeting structurally dynamic biomolecules, such as intrinsically disordered proteins.

In this synthetic study, a gold-catalyzed cascade cyclization reaction for the construction of the caulerpin scaffold, suitable for the preparation of unsymmetrical caulerpin derivatives, was developed. The reaction proceeds through the formation of an α-imino gold(I) carbene from an azido-alkyne, followed by nucleophilic attack of an alkenylindole moiety on the gold carbene, leading to the formation of the bis-indole-fused 8-membered ring, the caulerpin core structure. The use of ethyl enol ether and a bulky phosphine ligand is suitable for successful ring closure at the desired position.

Recently, a chromatographic quantitative method using relative molar sensitivity (RMS), the so-called RMS method, was developed for the determination of target analytes in food additives, drugs, and supplements. By determining the RMS value of the analyte to a different reference compound, this method avoids the need for an analytical standard of the analyte itself to plot calibration curves for quantification. In this collaborative study performed by 10 laboratories, we demonstrated the robustness and reliability of the RMS method in the quantitative analysis of chlorogenic acid (5-O-caffeoylquinic acid, 5CQA) in apple juice. Reagent-grade 5CQA derived from natural sources is commercially available, but its purity, stability, and hygroscopic properties still need to be clarified. Therefore, there is always a risk of bias in the quantitative results, even when the calibration curve is prepared using reagent-grade 5CQA as the analytical standard. The RMS method overcomes this problem by using caffeic acid (CA) with high purity and stability as a reference compound. Prior to the collaborative study, a laboratory documented the standard operating procedure for method validation, which was then implemented in all laboratories to determine the RMS value of 5CQA to CA and quantify 5CQA in five apple juice samples. A comparison between the results obtained using a calibration curve and the RMS method validates the RMS method using CA as a reference compound for the quantitative analysis of 5CQA without an analytical standard.