Chemical & pharmaceutical bulletin最新文献

Immunoglobulin G (IgG)-binding peptides have been widely used in medicinal chemistry, particularly in the preparation of homogeneous antibody-drug conjugates (ADCs). The dissociation constant (K_d) and kinetic parameters (k_on and k_off) are critical determinants of peptide performance in such applications. In this study, we conducted a structure-activity relationship (SAR) analysis of the IgG-binding peptide 15-IgBP, focusing on Asp3, Tyr6, and Thr15, to identify more potent derivatives with favorable binding affinities and kinetic profiles. Peptides with appropriately tuned ionic structures exhibited rapid binding and release properties, whereas hydrophobic substitutions in solvent-exposed regions led to slower dissociation. By integrating these SAR findings, we identified the optimized affinity peptides, IAPG-2 and IAPG-3, with sub-nanomolar binding affinities (K_d = 0.753 and 0.705 nM, respectively).

Hyaluronan (HA) is a commonly used material in cosmetics and pharmaceuticals because of its various pharmacological activities. However, because of its large molecular weight, HA penetrates the skin very poorly and most of it remains on the skin surface. Thus, topically applied HA could not be expected to function biologically in the skin. However, we have confirmed that HA tetrasaccharides (HA4), which is the smallest unit of HA, penetrate into the skin by passive diffusion and affect epidermal metabolism. Topical treatment of HA4 rescues the epidermal damage caused by long-term UVA irradiation. Furthermore, various biological functions of HA4 to maintain healthy skin was observed in cell culture studies. This review describes the skin permeability of HA4 and how it contributes to healthy skin.

The δ-opioid receptor (DOR) continues to attract attention as a therapeutic target for the development of safer analgesics due to its ability to mediate pain relief with a lower risk of adverse effects compared to the μ-opioid receptor (MOR). Building upon our previous findings on KNT-127, a DOR-selective agonist with a morphinan scaffold, this study further explores the structure-signal relationships between quinoline ring modifications and the signaling bias toward Gi-protein activation while minimizing β-arrestin-2 recruitment. Our findings highlight the critical role of the 5'-position in modulating signaling bias. Bulky hydrophobic substituents, such as isopropoxy and cyclohexanoxy groups, effectively reduce β-arrestin-2 recruitment without compromising DOR binding affinity or Gi-protein activation. Molecular-docking and molecular dynamics simulations provided mechanistic insights, showing that these modifications change ligand interactions with the V281^6.55-W284^6.58-L300^7.35 sub-pocket, thus selectively favoring Gi-protein signaling. These insights clarify the key interactions for the signaling bias in DOR agonists, offering a new framework for the design of DOR-targeted therapies with an improved therapeutic profile.

In screening for antibacterial agents from co-cultures of Mycobacterium smegmatis and microbial resources, such as actinomycetes and fungi, the known hydroxyquinone antibiotic griseorhodin A (1) was isolated from a co-culture of actinomycete strain TMPU-20A002 and M. smegmatis. Compound 1 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE), with minimum inhibitory concentrations of 0.25 and 2.0 μg/mL, respectively. In silkworm infection models with MRSA and VRE, 1 exhibited therapeutic efficacy, with ED₅₀ values of 2.5 and 18 μg/larva·g, respectively. A pharmacokinetic analysis of silkworms revealed an elimination half-life of 4.4 h in the hemolymph, indicating a favorable metabolic profile. This is the first in vivo evaluation of griseorhodin A, including its pharmacological activity and metabolic behavior, and it highlights its potential as a candidate for the development of novel antibacterial agents.

The δ-opioid receptor (DOR) is a promising target for developing novel analgesics due to its lower risk of causing side effects compared to the μ-opioid receptor (MOR), which is commonly associated with dependence, respiratory depression, and other adverse effects. KNT-127, a DOR-selective agonist with a morphinan skeleton, offers analgesic and antidepressant benefits without inducing convulsions at therapeutic doses, unlike the conventional DOR agonist SNC80. While previous studies have suggested that KNT-127 exhibits reduced β-arrestin recruitment, a signaling pathway implicated in adverse opioid effects, the ligand structural basis for this biased signaling remains unclear. In this study, we explored the structure-signal relationships of KNT-127, focusing on its quinoline moiety, which is known to serve as an address domain responsible for DOR selectivity. Modifying the quinoline moiety by removing the aromatic rings reduced DOR selectivity and potency in relation to G-protein activation while diminishing both the potency and efficacy of β-arrestin recruitment. These results suggest that the morphinan skeleton is critical for reduced β-arrestin recruitment, while the quinoline moiety differentially modulates G-protein activation and β-arrestin recruitment. Together, our study expands the message-address concept, previously limited to receptor selectivity, by providing structural insights into the G-protein-biased agonism of DOR agonists, thereby guiding the design of safer DOR-targeting therapeutics.

The purpose of the present study was to predict the intra-individual variability (%CV_intra) values of C_max using observed parameters of physicochemical and pharmacokinetic for a variety of formulations. A database was used to summarize the parameters of clinical bioequivalence (BE) studies of oral drugs, including the highest dose tablets, orally disintegrating tablets (ODT), and capsules (278 formulations [238 compounds]). As explanatory variables, %CV_intra, inter-individual variability (%CV_inter), absolute bioavailability (BA), T_max, t_1/2, dose number (Do), and dissolution rate (D%) were selected. Explanatory variables correlated with %CV_intra were identified by multivariate analysis and grouped quantitatively by K-means clustering analysis. The %CV_intra predictions compared three models of multiple regression, boosting tree, and neural network. In the neural network, the coefficient of determination (R²) and the root mean square error (RMSE) were the best, with good correlation between the predicted and observed values of the test data (R² = 0.69). The explanatory variables used in this study are readily available from the literature of reference formulation and in vitro measurement. Therefore, predicting %CV_intra for C_max without conducting pilot studies is useful for clinical planning in the early stages of generic drug development. We believe that we could further contribute to speeding up and reducing the cost of generic drug development.

New nucleoside derivatives containing the imidazole (Imd), pyridine or pyrimidine catalytic group were designed for site-specific acetylation of 2'-OH of the RNA ribose moiety. When the RNA substrate was acetylated in the presence of acetic anhydride under alkaline conditions, Probe (Imd) containing the imidazole catalytic group acetylated with a high selectivity to the 2'-OH of the uridine opposite the catalytic nucleotide. Probe (Py-4N) containing the pyridine group showed a higher catalytic activity under neutral conditions with a high selectivity for the 2'-OH group of the 5' side of the uridine opposite the catalytic nucleotide in about 80% modification yield within 10 min. This study has shown that the oligodeoxynucleotide incorporating the new nucleotide derivative with the catalytic group can be a useful tool for site-selective acetylation of RNA 2'-OH.

Mini-tablets (MTs) allow for dosage adjustments according to children's weight and age. However, it is difficult to manufacture MTs with robust physical properties, and various formulation techniques are required. Adding cellulose nanofiber (CNF), a highly functional biomass material, to MTs improved the hardness and disintegration; however, the large variation in the weight and drug content of the resulting MTs remained a challenge. Therefore, this study analyzed the physical properties of CNF-containing MTs of different particle sizes and evaluated the effect of the particle size on MT manufacturing. CNF₃₀₀, with an average particle size of approximately 300 µm, was pulverized to prepare CNF₁₀₀, averaging 100 µm. The formulation included CNF (10, 30, and 50%), lactose hydrate, paracetamol, and magnesium stearate. The pharmaceutical powders mixed were loaded into a rotary tablet press equipped with a 3-mm multiple-tip tooling and compressed at 2, 5, and 8 kN forces. CNF₁₀₀-containing MTs were manufactured via direct powder compression, and they showed lower variations in weight and drug content than those containing CNF₃₀₀. The tensile strength of MTs containing CNF₁₀₀ was smaller than that of those containing CNF₃₀₀; however, a strength of ≥1 MPa (corresponding to ≥30 N hardness of a regular tablet) was obtained by setting the compression force to ≥5 kN. The MTs containing 30% CNF₁₀₀ disintegrated in ≤30 s, regardless of the compression force. Thus, using smaller CNF particle sizes enabled the manufacturing of an orally disintegrating MT with adequate hardness and disintegration properties while also minimizing variations in MT weight and drug content.

Lysosome-targeting chimera (LYTAC) efficiently degrades specific membrane proteins. In a previous study, we synthesized and reported human epidermal growth factor receptor 2 (HER2)-LYTAC (that induces the degradation of HER2 protein using DNA aptamers that binds to insulin-like growth factor receptor 2 and HER2). In this study, we designed and synthesized linker-length-modified HER2-LYTAC derivatives with varying distances between the DNA aptamers and assessed their protein degradation-inducing activity. The results revealed that HER2 degradation varied significantly with the linker length. Notably, HL5L-HER2-LYTAC with a 5-bp longer linker than that of the original HER2-LYTAC-exhibited equivalent or enhanced activity and significantly inhibited the proliferation of HER2-positive cancer cells. This is the first study to assess the effect of linker length in designing LYTAC molecules using bispecific DNA aptamers and offers valuable insights into the molecular design of nucleic acid-based LYTACs.

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 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.