Search

Abstract Natural products, while valuable for drug discovery, encounter limitations like uncertainty in targets and toxicity. As an important active ingredient in traditional Chinese medicine, celastrol exhibits a wide range of biological activities, yet its mechanism remains unclear. In this study, they introduced an innovative “Degradation‐based protein profiling (DBPP)” strategy, which combined PROteolysis TArgeting Chimeras (PROTAC) technology with quantitative proteomics and Immunoprecipitation‐Mass Spectrometry (IP‐MS) techniques, to identify multiple targets of natural products using a toolbox of degraders. Taking celastrol as an example, they successfully identified its known targets, including inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ), phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PI3Kα), and cellular inhibitor of PP2A (CIP2A), as well as potential new targets such as checkpoint kinase 1 (CHK1), O‐GlcNAcase (OGA), and DNA excision repair protein ERCC‐6‐like (ERCC6L). Furthermore, the first glycosidase degrader is developed in this work. Finally, by employing a mixed PROTAC toolbox in quantitative proteomics, they also achieved multi‐target identification of celastrol, significantly reducing costs while improving efficiency. Taken together, they believe that the DBPP strategy can complement existing target identification strategies, thereby facilitating the rapid advancement of the pharmaceutical field.

The field of epigenetics pertains to alterations in gene function that are inherited without changes in the DNA sequence, including histone modifications, post-translational modifications of amino acids, and covalent modifications of DNA bases. These alteration pathways modulate the transformation of genotypes into specific phenotypes. Epigenetics plays major roles in cell growth, development, and differentiation by dynamically regulating gene transcription and ensuring genomic stability. This regulation is performed by three key players: writers, readers, and erasers. In recent years, epigenetic proteins have been found to have crucial roles in epigenetic regulation, and have become important targets in drug research and development. Although targeted therapy is an essential treatment strategy, the effectiveness of targeted drugs is often limited by drug resistance, thus posing a major dilemma in clinical practice. Targeted protein degradation technologies, including proteolysis-targeting chimeras (PROTACs), have great potential in overcoming drug resistance and targeting undruggable targets. PROTACs are gaining increasing attention in the treatment of various epigenetic diseases. In this review, we summarize recently developed degraders targeting epigenetic readers, writers, and erasers. Additionally, we outline new applications for epigenetic protein degraders. Finally, we address several unresolved challenges in the PROTAC field, and suggest potential solutions from our perspective. As the field continues to advance, the integration of these innovative methods holds great promise in addressing the challenges associated with PROTAC development.

Tylophorine has diverse biological activities; however, the stability, solubility, and central nervous system toxicity have severely limited use of tylophorine. The gem -dimethyl group is an organic chemistry functional group that consists of two methyl groups bonded to the same carbon atom. This feature has gained significant attention in medicinal chemistry due to its unique properties and potential applications in drug design. We applied a new photoredox methodology to tylophorine modification, resulting in a series of gem-dimethyl tylophorine analogues. Among the analogues, compound 4b demonstrated promising activity against a wide range of tumor cell lines and exhibited significantly improved drug-like properties, including enhanced solubility and stability. Compound 4b showed an exceptional inhibitory effect (7.8 nM) against a C481S mutation-induced ibrutinib-resistant non-Hodgkin’s lymphoma cell line, as well as primary tumor cell lines obtained from patients. Importantly, compound 4b exhibited significantly reduced anti-proliferative activity against the normal cell line tested, indicating the potential for an enhanced therapeutic window for compound 4b . Based on these early-stage data, we believe that our study provides a solid foundation for the development of new therapeutic agents for potential drug-resistant cancer treatment in the near future.

ABSTRACTCandida albicans is an important opportunistic pathogenic fungus that frequently causes serious systemic infection in humans. Due to the vital roles of biofilm formation and the yeast-to-hypha transition in the infection process, we have selected a series of diaryl chalcogenides and tested their efficacy against C. albicans SC5314 pathogenicity by the inhibition of biofilm formation and the yeast-to-hypha transition. The compounds 5-sulfenylindole and 5-selenylindole were found to have excellent abilities to inhibit both biofilm formation and hyphal formation in C. albicans SC5314. Intriguingly, the two leading compounds also markedly attenuated C. albicans SC5314 virulence in human cell lines and mouse infection models at micromolar levels. Furthermore, our results showed that the presence of the compounds at 100 µM resulted in a marked decrease in the expression of genes involved in the cAMP-PKA and MAPK pathways in C. albicans SC5314. Intriguingly, the compounds 5-sulfenylindole and 5-selenylindole not only attenuated the cytotoxicity of Candida species strains but also showed excellent synergistic effects with antifungal agents against the clinical drug-resistant C. albicans strain HCH12. The compound 5-sulfenylindole showed an obvious advantage over fluconazole as it could also restore the composition and richness of the intestinal microbiota in mice infected by C. albicans. Together, these results suggest that diaryl chalcogenides can potentially be designed as novel clinical therapeutic agents against C. albicans infection. The diaryl chalcogenides of 5-sulfenylindole and 5-selenylindole discovered in this study can provide new direction for developing antifungal agents against C. albicans infection.

Abstract Candida albicans is an important human fungal pathogen. Our previous study disclosed that aryloxy‐phenylpiperazine skeleton was a promising molecule to suppress C. albicans virulence by inhibiting hypha formation and biofilm formation. In order to deeply understand the efficacy and mechanism of action of phenylpiperazine compounds, and obtain new derivatives with excellent activity against C. albicans, hence, we synthesized three series of (1‐heteroaryloxy‐2‐hydroxypropyl)‐phenylpiperazines and evaluated their inhibitory activity against C. albicans both in vitro and in vivo in this study. Compared with previously reported aryloxy‐phenylpiperazines, part of these heteroaryloxy derivatives improved their activities by strongly suppressing hypha formation and biofilm formation in C. albicans SC5314. Especially, (9H‐carbazol‐4‐yl)oxy derivatives 25, 26, 27 and 28 exhibited strong activity in reducing C. albicans virulence in both human cell lines in vitro and mouse infection models in vivo. The compound 27 attenuated the virulence of various clinical C. albicans strains, including clinical drug‐resistant C. albicans strains. Moreover, additive effects of the compound 27 with antifungal drugs against drug‐resistant C. albicans strains were also discussed. Furthermore, the compound 27 significantly improved the composition and richness of the faecal microbiota in mice infected by C. albicans. These findings indicate that these piperazine compounds have great potential to be developed as new therapeutic drugs against C. albicans infection.

Abstract PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article “PROTACs: great opportunities for academia and industry” in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.

ABSTRACT Burkholderia cenocepacia is a human opportunistic pathogen that mostly employs two types of quorum-sensing (QS) systems to regulate its various biological functions and pathogenicity: the cis-2-dodecenoic acid (BDSF) system and the N-acyl homoserine lactone (AHL) system. In this study, we reported that oridonin, which was screened from a collection of natural products, disrupted important B. cenocepacia phenotypes, including motility, biofilm formation, protease production, and virulence. Genetic and biochemical analyses showed that oridonin inhibited the production of BDSF and AHL signals by decreasing the expression of their synthase-encoding genes. Furthermore, we revealed that oridonin directly binds to the regulator RqpR of the two-component system RqpSR that dominates the above-mentioned QS systems to inhibit the expression of the BDSF and AHL signal synthase-encoding genes. Oridonin also binds to the transcriptional regulator CepR of the cep AHL system to inhibit its binding to the promoter of bclACB. These findings suggest that oridonin could potentially be developed as a new QS inhibitor against pathogenic B. cenocepacia. IMPORTANCE Burkholderia cenocepacia is an important human opportunistic pathogen that can cause life-threatening infections in susceptible individuals. It employs quorum-sensing (QS) systems to regulate biological functions and virulence. In this study, we have identified a lead compound, oridonin, that is capable of interfering with B. cenocepacia QS signaling and physiology. We demonstrate that oridonin suppressed cis-2-dodecenoic acid (BDSF) and N-acyl homoserine lactone (AHL) signal production and attenuated virulence in B. cenocepacia. Oridonin also impaired QS-regulated phenotypes in various Burkholderia species. These results suggest that oridonin could interfere with QS signaling in many Burkholderia species and might be developed as a new antibacterial agent.

Summary Candida albicans is a common human fungal pathogen. The previous study revealed that quinone compounds showed antimicrobial activity against C. albicans by inhibiting cell growth. However, it was unclear whether quinones have other antifungal effects against C. albicans in addition to fungicidal effects. In this study, we assessed the inhibitory activity of a total of 25 quinone compounds against C. albicans morphological transition, which is essential for the pathogenicity of C. albicans. Several quinones exhibited strong inhibition of mycelium formation by C. albicans SC5314. Three leading compounds, namely hypocrellins A, B and C, also exhibited marked attenuation of C. albicans SC5314 virulence in both human cell lines and mouse infection models. These three compounds significantly suppressed the proliferation of C. albicans SC5314 cells in a mouse mucosal infection model. Intriguingly, hypocrellins not only attenuated the cytotoxicity of a nystatin‐resistant C. albicans strain but also showed excellent synergistic effects with antifungal agents against both wild‐type C. albicans SC5314 and the drug‐resistant mutant strains. In addition, hypocrellins A, B and C interfered with the biological functions and virulence of various clinical Candida species, suggesting the promising potential of these compounds for development as new therapeutic agents against infections caused by Candida pathogens.

Quorum sensing (QS) is widely employed by bacterial cells to control gene expression in a cell density-dependent manner. A previous study revealed that anthranilic acid from Ralstonia solanacearum plays a vital role in regulating the physiology and pathogenicity of R. solanacearum. We reported here that anthranilic acid controls the important biological functions and virulence of R. solanacearum through the receptor protein RaaR, which contains helix-turn-helix (HTH) and LysR substrate binding (LysR_substrate) domains. RaaR regulates the same processes as anthranilic acid, and both are present in various bacterial species. In addition, anthranilic acid-deficient mutant phenotypes were rescued by in trans expression of RaaR. Intriguingly, we found that anthranilic acid binds to the LysR_substrate domain of RaaR with high affinity, induces allosteric conformational changes, and then enhances the binding of RaaR to the promoter DNA regions of target genes. These findings indicate that the components of the anthranilic acid signaling system are distinguished from those of the typical QS systems. Together, our work presents a unique and widely conserved signaling system that might be an important new type of cell-to-cell communication system in bacteria.

In this work, polyacrylonitrile/aminated polymeric nanosphere (PAN/APN) nanofibers were prepared by electrospinning of monodispersed aminated polymeric nanospheres (APNs) for removal of Cr(VI) from aqueous solution. Characterization results showed that obtained PAN/APNs possessed nitrogen functionalization. Furthermore, the adsorption application results indicated that PAN/APN nanofibers exhibited a high adsorption capacity of 556 mg/g at 298 K for Cr(VI) removal. The kinetic data showed that the adsorption process fits the pseudo-second order. A thermodynamic study revealed that the adsorption of Cr(VI) was spontaneous and endothermic. The coexisting ions Na+, Ca2+, K+, Cl−, NO3− and PO43− had little influence on Cr(VI) adsorption, while SO42− in solution dramatically decreased the removal performance. In the investigation of the removal mechanism, relative results indicated that the adsorption behavior possibly involved electrostatic adsorption, redox reaction and chelation. PAN/APN nanofibers can detoxify Cr(VI) to Cr(III) and subsequently chelate Cr(III) on its surface. The unique structure and nitrogen functionalization of PAN/APN nanofibers make them novel and prospective candidates in heavy metal removal.

The co-application of biochar and fertiliser has emerged as a strategy for improving soil quality and crop growth; however, the impact of the type of fertiliser added with biochar to the soil on leaching and retention of nutrients is not well studied. In this study, a leaching experiment was undertaken using a series of column lysimeters incorporating a wheat straw biochar (WSB) and two fertiliser types—chemical fertiliser (CF), or rock mineral fertiliser (MF). The results showed that CF and MF leached a similar amount of NH4+ with or without WSB, but the NO3– leaching occurred from CF-treated soil which was decreased by CF + WSB application. In contrast, NO3– leaching was not affected by WSB in MF-treated soil. Both CF and MF with or without WSB increased the cumulative leaching of P and K. Nevertheless, WSB application increased soil P and K contents after leaching, which was attributed to intrinsic nutrient release from biochar. Shoot growth and P and K uptake also increased with biochar amendment, whereas root growth and N uptake did not change. Therefore, the results highlight that biochar addition can improve nutrient retention and plant growth by reducing nutrient leaching, mainly dependent on biochar and fertiliser type combination used. It suggests that the adsorption properties of biochar for nutrient retention and subsequent release need to know before their broad application to soils as amendments.

We report the first preliminary and extensive study on the solution self-assembly behaviors of poly(vinylidene fluoride)–b-polystyrene (PVDF–PS) block copolymers. The two PVDF–PS polymers we examined have the same length of PVDF block with number averaged repeating unit of 180, but distinctly different lengths of PS block with number averaged repeating unit of 125 and 1202. The self-assembly experiments were carried out in a series of mixture solutions containing a good solvent N,N-dimethylformamide and a selective solvent with different ratios. Our results showed that the self-assembly process was greatly affected by the two factors we examined, i.e. the length of the PS block and the solvent composition. We hope that our study could stimulate more research on the self-assembly of PVDF-containing polymers in solution. Keywords: Self-assembly, Block copolymers, Poly(vinylidene fluoride)

Anaerobic dechlorination of chlorophenols often subjects to their toxicity and recalcitrance, presenting low loading rate and poor degradation efficiency. In this study, in order to accelerate p-chlorophenol (p-CP) reduction and extracellular electron transfer in an anaerobic system, three iron-oxide nanoparticles, namely hematite, magnetite and ferrihydrite, were coupled into an anaerobic system, with the performance and underlying role of iron-oxide nanoparticles elucidated. The reductive dechlorination of p-CP was notably improved in the anaerobic systems coupled by hematite and magnetite, although ferrihydrite did not plays a positive role. Enhanced dechlorination of p-CP in hematite or magnetite coupled anaerobic system was linked to the obvious accumulation of acetate, lower oxidation–reduction potential and pH, which were beneficial for reductive dechlorination. Electron transfer could be enhanced by Fe2+/Fe3+ redox couple on the iron oxides surface formed through dissimilatory iron-reduction. This study demonstrated that the coupling of iron-oxide nanoparticles such as hematite and magnetite could be a promising alternative to the conventional anaerobic reduction process for the removal of CPs from wastewater.

Candida albicans is a type of commensal fungi which causes serious infections in immunocompromised patients and contributes to high mortality. In the present study, we identified that the extract from Streptomyces olivaceus SCSIO T05 inhibited hypha and biofilm formation of C. albicans. Seven compounds were isolated and evaluated for their effects on the biological functions and virulence of C. albicans. Two leading compounds, compound 1 (sorbicillin) and compound 2 (3-methyl-N-(2′-phenethyl)-butyrylamide) were identified as exhibiting strong activity against C. albicans morphological transition, adhesion activity, cytotoxicity, and adhesion to human cells, in a dose-dependent manner. Notably, compound 2 inhibited C. albicans infection in mouse oral mucosal models. Transcriptomic analysis and real-time PCR results revealed that compound 2 most likely inhibited the biological functions of C. albicans cells by regulating the expression levels of HWP1, TEC1, ALS1, IFD6, and CSH1, which are associated with filament formation and cell adhesion. Our results suggest that the candidate compounds present excellent efficacy against C. albicans pathogenicity and that they can be developed as potential options for the clinical treatment of candidiasis.

Prussian blue and its analogues (PBA) based nanomaterials have been widely applied to removing pollutants in the recent years. However, easy aggregation and poor recycling largely limit their practical applications. In this work, spiderweb-like Fe-Co Prussian blue analogue/polyacrylonitrile (FCPBA/PAN) nanofibers were prepared by electrospinning and applied to degrading bisphenol-A (BPA) by activating peroxymonosulfate (PMS). Detailed characterization demonstrated that a high loading of FCPBA (86% of FCPBA in FCPBA/PAN) was successfully fixed on the PAN nanofibers. 67% of BPA was removed within 240 min when 500 mg·L−1 PMS and 233 mg·L−1 FCPBA/PAN were introduced in 20 mg·L−1 BPA solution at initial pH of 2.8. Electron paramagnetic resonance (EPR) and radical inhibition experiments were performed to identify the possible degradation mechanism. For comparison, a low loading of FCPBA nanofibers (0.6FCPBA/PAN nanofibers, 43% of FCPBA in FCPBA/PAN) were also prepared and tested the catalytic performance. The results showed that the activity of FCPBA/PAN was much higher than 0.6FCPBA/PAN. Furthermore, a FCPBA/PAN packed column was made as a reactor to demonstrate the reusability and stability of FCPBA/PAN nanofibers, which also exhibited the bright future for the industrial application. This work makes it possible to fabricate efficient PBA nanocatalysts with excellent recyclability and promotes the application of PBA in industrial areas.

Ralstonia solanacearum is a causative agent of bacterial wilt in many important crops throughout the world. How to control bacterial wilt caused by R. solanacearum is a major problem in agriculture. In this study, we aim to isolate the biocontrol agents that have high efficacy in the control of bacterial wilt. Three new bacterial strains with high antimicrobial activity against R. solanacearum GMI1000 were isolated and identified. Our results demonstrated that these bacteria could remarkably inhibit the disease index of host plant infected by R. solanacearum. It was indicated that strain GZ-34 (CCTCC No. M 2016353) showed an excellent protective effect to tomato under greenhouse conditions. Strain GZ-34 was characterized as Escherichia coli based on morphology, biochemistry, and 16S rRNA analysis. We identified that the main antimicrobial compounds produced by E. coli GZ-34 were cyclo(l-Pro-d-Ile) and cyclo(l-Pro-l-Phe) using electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR) analysis. The two active compounds also interfered with the expression levels of some pathogenicity-contributors of R. solanacearum. Furthermore, cyclo(l-Pro-l-Phe) effectively inhibited spore formation of Magnaporthe grisea, which is a vital pathogenesis process of the fungal pathogen, suggesting cyclic dipeptides from E. coli are promising potential antimicrobial agents with broad-spectrum activity to kill pathogens or interfere with their pathogenesis.