The new direction of drug development: Degradation of undruggable targets through targeting chimera technology.

Imbalances in protein and noncoding RNA levels in vivo lead to the occurrence of many diseases. In addition to the use of small molecule inhibitors and agonists to restore these imbalances, recently emerged targeted degradation technologies provide a new direction for disease treatment. Targeted degradation technology directly degrades target proteins or RNA by utilizing the inherent degradation pathways, thereby eliminating the functions of pathogenic proteins (or RNA) to treat diseases. Compared with traditional therapies, targeted degradation technology which avoids the principle of traditional inhibitor occupation drive, has higher efficiency and selectivity, and widely expands the range of drug targets. It is one of the most promising and hottest areas for future drug development. Herein, we systematically introduced the in vivo degradation systems applied to degrader design: ubiquitin-proteasome system, lysosomal degradation system, and RNA degradation system. We summarized the development progress, structural characteristics, and limitations of novel chimeric design technologies based on different degradation systems. In addition, due to the lack of clear ligand-binding pockets, about 80% of disease-associated proteins cannot be effectively intervened with through traditional therapies. We deeply elucidated how to use targeted degradation technology to discover and design molecules for representative undruggable targets including transcription factors, small GTPases, and phosphatases. Overall, this review provides a comprehensive and systematic overview of targeted degradation technology-related research advances and a new guidance for the chimeric design of undruggable targets.

2D LDH-MoS2 clay nanosheets: synthesis, catalase-mimic capacity, and imaging-guided tumor photo-therapy.

Owing to the hypoxia status of the tumor, the reactive oxygen species (ROS) production during photodynamic therapy (PDT) of the tumor is less efficient. Herein, a facile method which involves the synthesis of Mg-Mn-Al layered double hydroxides (LDH) clay with MoS2 doping in the surface and anionic layer space of LDH was presented, to integrate the photo-thermal effect of MoS2 and imaging and catalytic functions of Mg-Mn-Al LDH. The designed LDH-MoS2 (LMM) clay composite was further surface-coated with bovine serum albumin (BSA) to maintain the colloidal stability of LMM in physiological environment. A photosensitizer, chlorin e6 (Ce6), was absorbed at the surface and anionic layer space of LMM@BSA. In the LMM formulation, the magnetic resonance imaging of Mg-Mn-Al LDH was enhanced thanks to the reduced and acid microenvironment of the tumor. Notably, the ROS production and PDT efficiency of Ce6 were significantly improved, because LMM@BSA could catalyze the decomposing of the overexpressed H2O2 in tumors to produce oxygen. The biocompatible LMM@BSA that played the synergism with tumor microenvironment is a promising candidate for the effective treatment of cancer.

Development of Potent MALT1 Inhibitors Featuring a Novel "2-Thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one" Scaffold for the Treatment of B Cell Lymphoma.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) has emerged as a novel and promising therapeutic target for the treatment of lymphomas and autoimmune diseases. Herein, we reported a new class of MALT1 inhibitors featuring a novel "2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one" scaffold developed by structure-based drug design. Structure-activity relationship studies finally led to the discovery of MALT1 inhibitor 10m, which covalently and potently inhibited MALT1 protease with the IC50 value of 1.7 µM. 10m demonstrated potent and selective antiproliferative activity against ABC-DLBCL and powerful ability to induce HBL1 apoptosis. 10m also effectively downregulated the activities of MALT1 and its downstream signal pathways. Furthermore, 10m induced upregulation of mTOR and PI3K-Akt signals and exhibited a synergistic antitumor effect with Rapamycin in HBL1 cells. More importantly, 10m remarkably suppressed the tumor growth both in the implanted HBL1 and TMD8 xenograft models. Collectively, this work provides valuable MALT1 inhibitors with a distinct core structure.

Rapid Identification of Drug Mechanisms with Deep Learning-Based Multichannel Surface-Enhanced Raman Spectroscopy.

Rapid identification of drug mechanisms is vital to the development and effective use of chemotherapeutics. Herein, we develop a multichannel surface-enhanced Raman scattering (SERS) sensor array and apply deep learning approaches to realize the rapid identification of the mechanisms of various chemotherapeutic drugs. By implementing a series of self-assembled monolayers (SAMs) with varied molecular characteristics to promote heterogeneous physicochemical interactions at the interfaces, the sensor can generate diversified SERS signatures for directly high-dimensionality fingerprinting drug-induced molecular changes in cells. We further train the convolutional neural network model on the multidimensional SAM-modulated SERS data set and achieve a discriminatory accuracy toward 99%. We expect that such a platform will contribute to expanding the toolbox for drug screening and characterization and facilitate the drug development process.

Enzyme-Free Nucleic Acid Circuits for Fold-Change Detection.

Fold-change detection is widespread in sensory systems of various organisms. Dynamic DNA nanotechnology provides an important toolbox for reproducing structures and responses of cellular circuits. In this work, we construct an enzyme-free nucleic acid circuit based on the incoherent feed-forward loop using toehold-mediated DNA strand displacement reactions and explore its dynamic behaviors. The mathematical model based on ordinary differential equations is used to evaluate the parameter regime required for fold-change detection. After selecting appropriate parameters, the constructed synthetic circuit exhibits approximate fold-change detection for multiple rounds of inputs with different initial concentrations. This work is anticipated to shed new light on the design of DNA dynamic circuits in the enzyme-free environment.

Revisiting the effect of boiling on halogenated disinfection byproducts, total organic halogen, and cytotoxicity in simulated tap water.

Boiling is a widely adopted household tap water treatment method because of its ability to inactivate chlorine-resistant pathogenic bacteria, and to reduce certain groups of disinfection byproducts (DBPs). From a more comprehensive point of view, this study revisited the effect of boiling on four groups of 17 aliphatic DBPs and six groups of 44 aromatic DBPs in both simulated chlorinated and chloraminated tap water samples, with a special focus on the changes of total organic halogen (TOX) and cytotoxicity. Results showed that the concentrations of aliphatic DBPs substantially decreased during boiling via volatilization (trihalomethanes and chloral hydrate) and hydrolysis (haloacetamides) in chlorinated and chloraminated tap water samples. The concentrations of aromatic DBPs during boiling generally followed an increasing trend due to decarboxylation of polycarboxylic precursors in chlorinated tap water samples, and showed a first increasing and then decreasing trend in chloraminated tap water samples. A sharp decreasing of TOX occurred in the heating process of tap water samples from room temperature to 100 °C, and a relatively gentle decreasing was kept in the prolonged boiling process till 5 min. The most abundant DBP group in the tap water samples without boiling was trihalomethanes, and was replaced by haloacetic acids with boiling for 5 min. Continuous boiling for 5 min substantially reduced the cytotoxicity of chlorinated and chloraminated water samples by 52.6% and 21.3%, respectively. Reduction of cytotoxicity matched well with the reduction of TOCl (r = 0.907, P < 0.01), TOBr (r = 0.885, P < 0.01) and TOX (r = 0.905, P < 0.01), suggesting that the cytotoxicity reduction during boiling was mainly ascribed to the reduction of halogenated DBPs. Therefore, boiling of tap water to 100 °C was strongly recommended to reduce the potential health risks induced by tap water ingestion.

Exploring the Effects of Geographic Scale on Spatial Learning.

BACKGROUND: Investigating the relationship between the human body and its spatial environment is a critical component in understanding the process of acquiring spatial knowledge. However, few empirical evaluations have looked at how the visual accessibility of an environment affects spatial learning. To address this gap, this paper focuses on geographic scale, defined as the spatial extent visually accessible from a single viewpoint. We present two experiments in which we manipulated geographic scale using two perspectives, a ground level and an elevated view, in order to better understand the scale effect on spatial learning. Learning outcomes were measured using estimates of direction and self-reports of mental workload. RESULTS: In contrast to our hypothesis, we found few differences in spatial learning when comparing different perspectives. However, our analysis of pointing errors shows a significant interaction effect between the scale and spatial ability: The elevated perspective reduced the differences in pointing errors between low and high spatial ability participants in contrast to when participants learned the environment at ground level alone. Bimodal pointing distributions indicate that participants made systematic errors, for example, forgetting turns or segments. Modeling these errors revealed a unified alternative representation of the environment and further suggests that low spatial ability participants benefited more from the elevated perspective in terms of spatial learning compared to high spatial ability participants. CONCLUSIONS: We conclude that an increased geographic scale, which was accessible through an elevated perspective in this study, can help bridge the performance gap in spatial learning between low and high spatial ability participants.

Synthesis of a Clay-Based Nanoagent for Photonanomedicine.

Photo-induced cancer therapies, mainly including photothermal therapy (PTT) and photodynamic therapy (PDT), have attracted numerous attentions owing to the high selectivity, convenience, and few side effects. However, single PTT usually requires high laser power density, and single PDT usually needs a high photosensitizer dosage. Herein, a kind of composite nanocarrier based on clay (laponite)-polypyrrole (LP) nanodisks was synthesized via the in situ polymerization of pyrrole in the interlayer space of laponite. LP composite nanodisks were then coated with polyvinylpyrrolidone (PVP) to form the LP-PVP (LPP) composite nanodisks which show an excellent colloidal stability and in vitro and in vivo biocompatibility. The interlayer space of LPP can be further used for the loading of Chlorin e6 (Ce6), with an ultrahigh loading capacity of about 89.2%. Furthermore, the LPP nanocarrier can enhance the PDT effect of Ce6 under the irradiation of a 660 nm laser, through enhancing its solubility and cellular uptake amount. Besides, it was found that LPP nanodisks exhibit a more outstanding photothermal performance under a 980 nm near-infrared laser (NIR) than a 808 nm NIR laser, with the photothermal conversion efficiency of 45.7 and 27.7%, respectively. The in vitro and in vivo tumor therapy results evidently confirm that the Ce6-loaded LPP nanodisks have a combined tumor PTT and PDT effect, which can significantly suppress the tumor malignant proliferation.

MoS2-ALG-Fe/GOx hydrogel with Fenton catalytic activity for combined cancer photothermal, starvation, and chemodynamic therapy.

Starvation therapy (ST) and chemodynamic therapy (CDT) are emerging tumor therapy methods in recent years. In this study, a simple approach was reported to prepare MoS2 and glucose oxidase (GOx)-containing sodium alginate (ALG)-Fe3+ (MAF) hydrogel. In the hydrogel, there exists an enzymatic reaction to consume glucose to form hydrogen peroxide (H2O2), and a redox reaction between Fe3+ and MoS2 to form Fe2+ and MoO42-. The formed Fe2+ could be oxidized to Fe3+, which reacts with MAF hydrogel again to continuously produce Fe2+. The consumption of glucose resulted in an obvious tumor ST. Moreover, the produced Fe2+ induced a Fenton reaction to enable the persistent conversion of H2O2 to cytotoxic hydroxyl radicals (·OH) for the CDT of tumors. Together with the high photothermal transforming capability of MoS2, the hydrogel was used for the combined tumor photothermal therapy (PTT), ST, and CDT. This work provides a window for the safe use of enzymes for achieving high tumor therapeutic efficacy.