DNA-encoded library (DEL) technology has proven to be a powerful method for discovering novel inhibitors for diverse targets. Particularly when combined with machine learning (ML), the DEL-ML workflow expands the chemical space and enhances cost-effectiveness, offering new opportunities to find desired hit molecules. Heme oxygenase-1 (HO-1), primarily a heme-degrading enzyme, has been identified as a potential therapeutic target in diseases such as cancer and neurodegenerative disorders. Despite years of study, the HO-1 inhibitor toolbox remains limited. Here, we report the discovery of five series of novel scaffold HO-1 inhibitors using a DEL-ML workflow that emphasizes the model’s uncertainty quantification and its domain of applicability. The DEL-ML model demonstrated a strong ability to extrapolate to novel chemical spaces by identifying new structures. Approximately 33% of the predicted molecules, validated by biophysical assays, had a binding affinity of K¬D < 15 µM, with the strongest affinity being 141 nM. Fourteen tested molecules showed over 100-fold selectivity towards HO-1 over Heme oxygenase-2 (HO-2). These molecules are also structurally novel compared to the reported HO-1 inhibitors. Further, binding mode simulations via docking provided insights into the possible selectivity rationale of some selective series.
<div>Abstract<p>Vδ1T cells, a rare subset of γδT cells, hold promise for treating solid tumors. Unlike conventional T cells, they recognize tumor antigens independently of the MHC antigen presentation pathway, making them a potential “off-the-shelf” cell therapy product. However, isolation and activation of Vδ1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale clinical-grade manufacturing process for Vδ1T cells and validated the therapeutic potential of B7-H3 chimeric antigen receptor (CAR)–modified Vδ1T cells in treating solid tumors. Coexpression of IL2 with the B7-H3-CAR led to durable antitumor activity of Vδ1T cells <i>in vitro</i> and <i>in vivo</i>. In multiple subcutaneous and orthotopic mouse xenograft tumor models, a single intravenous administration of the CAR-Vδ1T cells resulted in complete tumor regression. These modified cells demonstrated significant <i>in vivo</i> expansion and robust homing ability to tumors, akin to natural tissue-resident immune cells. Additionally, the B7-H3-CAR-Vδ1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR–modified Vδ1T cells represent a promising strategy for treating solid tumors.</p><p><b>Significance:</b> A clinical-grade expansion protocol enabled generation of B7-H3–targeted CAR-Vδ1T cells with robust anticancer activity and a favorable safety profile, supporting the potential of CAR-Vδ1T cells as an “off-the-shelf” therapy for solid tumors.</p></div>
Using traditional Chinese medicine residues as raw materials, different biochars (BC) were prepared through oxygen-limited pyrolysis at 300 °C, 500 °C, and 700 °C, and BC was ball-milled to produce ball-milled biochar (BMC). Using these adsorbents to adsorb the allelopathic autotoxic substance quercetin. The physical and chemical properties of various biochars derived from traditional Chinese medicine residues were characterized using the Brunauer–Emmett–Teller-N2 surface areas (BET), scanning electron microscopy (SEM), Fourier transform IR spectroscopy (FTIR), X-ray diffraction (XRD), and Raman spectroscopy (Raman). The study investigated the effects of the initial pH value, different humic acid concentrations, and multiple adsorption–desorption experiments on the removal of quercetin from the solution. The article discusses the adsorption mechanism of quercetin in solution by biochar from a traditional Chinese medicine residue, based on the results of adsorption kinetics and adsorption isotherm fitting. The findings indicate that increasing the pyrolysis temperature reduces the oxygen-containing functional groups of BC, enhances the aromaticity, and stabilizes the carbon structure. The pore structure of BMC becomes more complex after ball milling, which increases the number of oxygen-containing functional groups on the surface. Among the samples tested, BMC700 exhibits the best adsorption performance, with an adsorption capacity of 293.3 mg·g–1 at 318 K. The adsorption process of quercetin by BMC700 follows the pseudo-second-order kinetic model and the Freundlich adsorption isotherm model. The process is primarily a form of multimolecular layer adsorption. Its mechanism involves the pore-filling effect, hydrogen-bonding interaction, electrostatic interaction, and π–π coexistence, as well as the yoke effect. Additionally, they are highly recyclable and show promise in addressing continuous cropping issues.
To date, RNA-targeted chemical matter is under explored due to a lack of robust screening assays. In this study, we present a novel RNA-targeted small molecule screening approach using a specialized DNA-encoded library (DEL). Our findings reveal that the specialized DEL library, called "DEL Zipper", can significantly reduce single-stranded DNA-RNA region interaction signals during various kinds of RNA selection. By performing the selection against both G-quadruplex, we have identified novel hits that interact with RNA targets and the results are validated through binding. This study demonstrates that the "DEL Zipper" method is a robust screening assay that has potential for discovering small molecule ligands for diverse RNA targets.
Abstract Vδ1T cells, a rare subset of γδT cells, hold promise for treating solid tumors. Unlike conventional T cells, they recognize tumor antigens independently of the MHC antigen-presentation pathway, making them a potential “off-the-shelf” cell therapy product. However, isolation and activation of Vδ1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale clinical-grade manufacturing process for Vδ1T cells and validated the therapeutic potential of B7-H3-CAR-modified Vδ1T cells in treating solid tumors. Co-expression of interleukin-2 with the B7-H3-CAR led to durable anti-tumor activity of Vδ1T cells in vitro and in vivo. In multiple subcutaneous and orthotopic mouse xenograft tumor models, a single intravenous administration of the CAR-Vδ1T cells resulted in complete tumor regression. These modified cells demonstrated significant in vivo expansion and robust homing ability to tumors, akin to natural tissue-resident immune cells. Additionally, the B7-H3-CAR-Vδ1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR-modified Vδ1T cells represent a promising strategy for treating solid tumors.
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