Bioorganic & Medicinal Chemistry最新文献

Alzheimer's disease currently affects over 44 million individuals worldwide. Inhibiting Aβ aggregation and preventing the formation of toxic Aβ oligomers were regarded as promising therapeutic approaches. Experimental studies demonstrated that 1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranose (PGG), a natural polyphenol enriched with gallate moieties, significantly inhibited Aβ₄₂ oligomerization and amyloid formation both in vitro and in vivo, underscoring its potential as a promising lead compound for AD therapy. Nevertheless, the detailed molecular mechanisms remained mostly unknown. Herein, we employed relevant biophysical methods to investigate the inhibitory effects of PGG and its analogs on Aβ₄₂ amyloid aggregation, particularly on oligomer formation, providing direct evidence for the influence of gallate moiety number on its inhibitory activity against Aβ₄₂ amyloid aggregation. Moreover, we further conducted 1500 ns all-atom MD simulations to explore how PGG inhibited Aβ amyloid aggregation. The simulations revealed that PGG promoted the adoption of a more loosely packed conformation of the Aβ₄₂ dimer, and completely prevented the helix-to-β-sheet conformational change. Moreover, the binding of PGG molecules to the Aβ₄₂ dimer resulted in the disruption of the inter-peptide interactions, and dramatically weakened the intra-peptide contacts. We observed that, apart from the usual hydrogen bonds and hydrophobic interactions, both π-π and cation-π interactions were also detected between specific residues of the Aβ₄₂ dimer and the gallate moieties of PGG. We believed that these results might provide novel insights into the mechanisms underlying the inhibitory effects of PGG on Aβ₄₂ amyloid aggregation and further support its potential for AD prevention and treatment.

Clostridioides difficile is an anaerobic bacterium that is responsible for most antibiotic-associated cases of diarrhea. Clostridioides difficile infection (CDI) begins with the ingestion of an environmentally stable spore that germinates within the GI tract if the concentration and composition of bile salts, ions, and amino acids are favorable. We have shown that the bile salt analog N-phenyl-cholan-24-amide (1) can inhibit spore germination and prevent CDI in animal models of infection. Unfortunately, 1, while stable in the gut of antibiotic-treated animals, is rapidly degraded by normal gastrointestinal microbiota to release cholate and aniline. This instability prevents its use as a prophylactic for CDI. To generate more stable bile salt analogs, we removed the amide by either reducing it to an amine or converting it into 5,6-fused heterocycles. We found that reduction of the amide to an amine resulted in a significant loss of activity, but cyclization to benzimidazole (6a), benzothiazole (6b), or benzoxazole (6c) gave anti-germinants with good IC₅₀ values. Changes in the sterane group to chenodeoxycholate and deoxycholate gave active compounds only for the benzimidazole series. Mice treated for 7 days with 6a and 6b showed no signs of toxicity up to 300 mg/kg/day. Compound 6b, but not 6a, was able to prevent CDI in a murine model of CDI when given at a dose of 50 mg/kg for three days. Examination of 6b showed that it was stable for 96 h in the presence of feces taken from healthy mice validating the hypothesis that replacing the amide with a bioisostere could increase the stability of the compound.

Through structure-based design to optimize protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) inhibitors, we developed two distinct conformational restriction strategies: intermolecular hydrogen bonding and cyclization. The hinge-binding carboxamide cyclized derivative B3 demonstrated potent enzymatic inhibition (IC₅₀ = 3.5 nM) and cellular CDK1 phosphorylation suppression (IC₅₀ = 65-114 nM), selectively inhibited proliferation of CCNE1-amplified cancer cells (IC₅₀ = 0.56-0.88 μM) through induction of γH2AX accumulation. Furthermore, compared to the first-in-class PKMYT1 inhibitor RP-6306, B3 exhibited enhanced solubility (176 vs 45 μM) and favorable in vivo metabolic stability (mouse clearance 58.2 vs 85.7 mL/min/kg), underscoring cyclization as a productive design strategy to improve drug-likeness of PKMYT1 inhibitors.

Here, we report the structure-guided identification pipeline of a novel PrP^C-binding peptide, PEP1, derived from Brucella abortus Hsp60 through computational docking. Computational modeling predicted that PEP1 engages the PrP^C binding interface with favorable binding energetics, motivating its experimental evaluation as a receptor-targeting ligand. Fusion of PEP1 to a model protein enabled receptor-mediated targeting to intestinal M-cell-associated regions and resulted in increased mucosal IgA and systemic IgG responses relative to the untargeted protein. Together, these findings establish PEP1 as a minimal peptide ligand that promotes receptor-mediated antigen uptake through M cells, demonstrating the utility of structure-guided approaches for discovering functional targeting peptides.

Hypochlorous acid (HClO), as a key component of endogenous reactive oxygen species, plays a critical role in endoplasmic reticulum (ER) homeostasis regulation. Its dynamic imbalance is closely associated with pathological processes such as neurodegenerative diseases and cancer. This study introduces a "turn-on" near-infrared fluorescent probe, XB-CTs, designed for the specific targeting and detection of hypochlorous acid (HClO) within the ER. It uses a dihydroxanthene-hemicyanine dye as the NIR fluorescent base, featuring an N,N-dimethylthiocarbamate group for quick, specific HClO detection, and a p-toluenesulfonamide group for ER targeting. The XB-CTs probe performs exceptionally well by emitting NIR fluorescence at 735 nm, avoiding biological autofluorescence interference. It is highly sensitive to HClO with a 0.141 μM detection limit and responds in 1 s. it specifically targets the ER in live cells, providing high signal-to-noise ratio imaging for real-time HClO detection. Additionally, it has been effectively used for stable fluorescence imaging of HClO in mice. This study provides a feasible detection tool for investigating ER oxidative stress processes, and its potential applications in biomedical research warrant further exploration and validation.

B-cell lymphoma 6 (BCL6) is a transcriptional repressor protein central to the development and maintenance of germinal centers (GCs) during the humoral immune response. BCL6 is often deregulated in diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin's lymphoma, and inhibition of the protein-protein interaction between BCL6 and corepressors has been implicated as a therapeutic strategy. Based on a previously identified small molecule binding site on the BCL6 BTB domain, we carried out a virtual screen and identified a set of high micromolar screening hits. One series was advanced to a low micromolar confirmed hit via iterative rounds of compound optimization guided by structure activity relationships and co-crystal structures. Overall, we were able to use a rational, structure-based drug design approach to identify and advance a novel series of pyrrolopyrimidinone BCL6 BTB inhibitors.