1. Shu-Yu Yang#, Ti-Ti Ying#, Tian-Hui Zhou, Yu-Tian Guan, Xu-Liang Xu, Hong Wang*, Bin Wei*. The Myxobacterial Genus Archangium: A Prolific and Underexploited Source of Bioactive Secondary Metabolites. Journal of Medicinal Chemistry. 2025.(https://doi.org/10.1021/acs.jmedchem.4c02203) IF：6.8

Abstract

The genus Archangium, a cryptic group of myxobacteria, is a rich source of diverse secondary metabolites. This study reviews the chemical structures and discovery history of 55 secondary metabolites, analyzing the relationship between the chemical structures of these compounds and their bioactivity profiles through molecular networking. Notably, 63.6% of the compounds exhibit potent antimicrobial (MIC < 1 μg/mL) and/or cytotoxic activities (IC50 < 1 μg/mL). Advances in the biosynthetic gene clusters and biosynthetic pathways of seven classes of identified compounds are also presented. Finally, genomic mining approaches are applied to analyze the potential for Archangium strains to synthesize analogs of identified bioactive natural products, uncovering that 98.7% of their secondary metabolic potential remains unexplored. This study highlights the vast potential of Archangium bacteria in synthesizing clade-specific novel secondary metabolites, particularly ribosomally synthesized and post-translationally modified peptide natural products, offering valuable insights for the targeted discovery and biosynthesis of new natural products from this genus.

2. Bin Wei#,*, Ti-Ti Ying#, Hua-Wei Lv#, Zhen-Yi Zhou, Hai Cai, Gang-Ao Hu, Hui-Min Liang, Wen-Chao Yu, Yan-Lei Yu, Ai-Li Fan, Kui Hong, Xing-Nuo Li*, Hong Wang*. Global analysis of fungal biosynthetic gene clusters reveals the diversification of diketopiperazine biosynthesis. Bioresource Technology (2025), 422: 132218. (https://doi.org/10.1016/j.biortech.2025.132218) IF：9.7

Abstract

Fungi are a vast reservoir of structurally diverse natural products, yet their biosynthetic potential remains underexplored. Here, we present the most comprehensive fungal biosynthetic gene cluster (BGC) atlas, comprising 303,983 BGCs predicted from 13,125 fungal genomes, revealing numerous underexplored taxa harboring extensive biosynthetic diversity. These BGCs were classified into 43,984 gene cluster families (GCFs), of which 99.6 % remain uncharacterized. Gene-centric analysis revealed the presence of 359 cyclodipeptide synthases (CDPSs) of three distinct subcategories and 9,482 nonribosomal peptide synthetases (NRPSs) responsible for diketopiperazine biosynthesis in the fungal BGC atlas. Notably, 304 type I CDPSs were exclusively found in Fusarium, with one confirmed to be responsible for the synthesis of cyclo(Leu-Ile) and cyclo(Pro-Leu). Bioinformatics analysis suggests that three newly identified indole diketopiperazine alkaloids, isolated from a marine-derived Aspergillus strain, are synthesized by an NRPS. This study presents the most comprehensive fungal BGC atlas and highlights the diversification of diketopiperazine biosynthesis in fungi.

3. Quan Xu, Ye-Qing Du, Pan-Pan Chen, Yili Sun, Ze-Nan Yang, Hui Zhang, Bencan Tang, Hong Wang, Jia Li*, Yue-Wei Guo*, Xu-Wen Li*. Computation assisted chemical study of photo-induced late-stage skeleton transformation of marine natural products towards new scaffolds with biological functions. Chinese Chemical Letters, 2025, 36(5): 110141. (https://www.sciencedirect.com/science/article/pii/S1001841724006600?dgcid=coauthor) IF：9.4

Abstract

A computer-assisted chemical investigation of an intriguing photoreaction of norditerpenoids (3‒7) has been first reported, leading to not only their biomimetic conversion, but also the generation of several new products with uncommon 4,14-dioxabicyclo[10.2.1]pentadecane scaffold (8, 9, 12‒14). In bioassay, compounds 10 and 15 exhibited significant stimulation of GLP-1 secretion. This study has given an insight for the application of computational methods on the late-stage skeleton transformation of complex natural products towards new bioactive compounds.

4. Yanlei Yu#, Honggang Wang#, Xiaoshu Jin#, Wenjing Huang, Yunjie Zhao, Ningning Wang, Dongze Lu, Bin Wei, Hong Wang*. Structural characterization of Dendrobium officinale polysaccharides and their regulation effect on intestinal microbiota during in vitro fermentation. Polymers 2025, 17(6), 727. (https://doi.org/10.3390/polym17060727). IF：4.7

Polysaccharides derived from Dendrobium officinale have been demonstrated to exhibit metabolic regulatory properties. However, the correlation between their structure and function, particularly their mechanism of action through gut microbiota, remains underexplored. This study systematically elucidates the structural characteristics of Dendrobium officinale polysaccharide (DOP) from the Guizhou (GZ) and Zhejiang (ZJ) provinces of China using nuclear magnetic resonance (NMR) and a series of chromatographic analyses, revealing their unique molecular features. Additionally, the metabolic regulatory activities were assessed through α-glucosidase inhibitory assay and in vitro intestinal flora activity assay. The findings not only uncover a novel mechanism by which DOPs regulate metabolism through gut microbiota but also provide a crucial theoretical basis for the application of DOPs in functional foods and pharmaceutical development.

5. Buddha Bahadur Basnet, Zhen-Yi Zhou, Bin Wei*, Hong Wang*. Advances in AI-based strategies and tools to facilitate natural product and drug development. Critical Reviews in Biotechnology, 2025. (https://doi.org/10.1080/07388551.2025.2478094) IF：8.2

Abstract

Natural products and their derivatives have been important for treating diseases in humans, animals, and plants. However, discovering new structures from natural sources is still challenging. In recent years, artificial intelligence (AI) has greatly aided the discovery and development of natural products and drugs. AI facilitates to: connect genetic data to chemical structures or vice-versa, repurpose known natural products, predict metabolic pathways, and design and optimize metabolites biosynthesis. More recently, the emergence and improvement in neural networks such as deep learning and ensemble automated web based bioinformatics platforms have sped up the discovery process. Meanwhile, AI also improves the identification and structure elucidation of unknown compounds from raw data like mass spectrometry and nuclear magnetic resonance. This article reviews these AI-driven methods and tools, highlighting their practical applications and guide for efficient natural product discovery and drug development.

6. Ti-Ti Ying#, Hao-Qiang Hu#, Xiao-Wen Wu, Xu-Liang Xu, Jian Lv, Shu-Ning Zhang, Hong Wang, Wei Hou*, Bin Wei*, Guo-Wu Rao*. Optimized ebselen derivatives as novel potent Escherichia coli β-glucuronidase covalent allosteric inhibitors. European Journal of Medicinal Chemistry (2025), 290: 117571. (https://doi.org/10.1016/j.ejmech.2025.117571) IF: 6.0

Abstract

Gut microbial β-glucuronidase (GUS) plays a key role in metabolizing compounds and influencing disease and drug metabolism, highlighting the need for potent inhibitors to improve drug efficacy and intestinal health. To identify Escherichia coliβ-glucuronidase (EcGUS) inhibitors, we designed and synthesized fifty 1,2-benzoselenazol-3-one (BSEA) derivatives using a bioisosterism strategy. Among these, twenty-five BSEA derivatives demonstrated greater inhibitory efficacy than the most potent known EcGUS inhibitor, amoxapine (AMX), with compound 49showing the strongest activity, achieving an IC50 of 12.9 nM. Structure–inhibitory activity relationship analysis suggested that modifications such as adding benzene rings or nitrogenous heterocycles to the BSEA scaffold enhanced inhibitory activity, influenced by the type and position of substituents. The LC−MS analysis confirmed that compounds 31 and 49 covalently modify Cys197 in EcGUS, and additional covalent linkage of compound 49 was observed on Cys28 and Cys443. In addition, the jump dilution assays proved that compounds 31 was irreversible covalent inhibitors, and its kinetic parameter kinact/KI were determined to be 21292.9 M−1s−1. The compounds 49 was reversible covalent inhibitors and its apparent steady-state inhibition constant Ki∗app were determined to be 23.33 nM. Molecular docking predicted specific interactions, such as hydrogen bonds involving Se and the pyrazole NH of compound 49 with Cys28 and Cys449, which may contribute to its inhibitory action. This study reports the first discovery of covalent inhibitors for EcGUS, with optimized BSEA derivatives acting as novel allosteric covalent inhibitors, revealing structure-activity relationships and molecular determinants that establish their potential in drug development.

7. Yi Hua,# Gangao Hu,# Titi Ying, Jiangwei Pan, Zhenyi Zhou, Cuixian Zhang,* Hong Wang,* and Bin Wei*.  The Pathogenic Fungal Genus Corynespora: A Prolific Source of Bioactive Secondary Metabolites. Journal of Natural Products. (https://doi.org/10.1021/acs.jnatprod.5c00145)

Abstract

In this perspective, we examine the chemical structures and biological activities of 55 secondary metabolites isolated from the pathogenic fungal genus Corynespora. Over 20% of these compounds demonstrate bioactivities, including antibacterial, anticancer, enzyme inhibition, and others. Bioinformatic analysis reveals that Corynespora possesses a high potential for encoding PKS-I and NRPS natural products, including many clade-specific metabolites, and only 2.1% of biosynthetic gene cluster families are associated with known secondary metabolites. This study underscores the significant, unexplored potential of Corynespora strains for synthesizing novel secondary metabolites, providing valuable insights into the targeted discovery and biosynthesis of novel natural products from this genus.

8. Cai-Ling Yang#, Pan-Pan Wang#, Zhen-Yi Zhou, Xiao-Wen Wu, Yi Hua, Jian-Wei Chen, Hong Wang*, Bin Wei*. Discovery of naturally inspired antimicrobial peptides using deep learning. Bioorganic Chemistry (2025), 160: 108444. (https://doi.org/10.1016/j.bioorg.2025.108444)

Abstract

Non-ribosomal peptides (NRPs) are promising lead compounds for novel antibiotics. Bioinformatic mining of silent microbial NRPS gene clusters provide crucial insights for the discovery and de novo design of bioactive peptides. Here, we describe the efficient discovery and antibacterial evaluation of novel peptides inspired by metabolite scaffolds encoded by NRPS gene clusters from 216,408 bacterial genomes. In total, 335,024 NRPS gene clusters were identified and dereplicated, yielding 328 unique peptide scaffolds. Using deep learning-based scoring, five antimicrobial peptide candidates (P1–P5) were synthesized via solid-phase chemical synthesis. Among them, peptide P2 exhibited potent antibacterial activity with MIC50 values of 1–2 μM against two pathogenic strains. Subsequent amino acid optimization guided by deep learning algorithms produced P2.2, a derivative with significantly enhanced antibacterial activity. Mechanistic studies revealed that P2.2 disrupts bacterial membranes and increases permeability by modulating proteins involved in the type VI and III secretion systems. Furthermore, P2.2 demonstrated synergistic effects when combined with conventional antibiotics and exhibited reduced hemolytic activity, improving its therapeutic potential. These findings underscore the immense potential of deep learning to accelerate the discovery of naturally inspired antimicrobial peptides from silent biosynthetic gene clusters.

9. Bing-Cheng Dong#, Fen Liu#, Gang-Ao Hu, Wen-Chao Yu, Zi-Yang Li, Yu-Tian Guan, Wen-Wen Zhang, Hong Wang*, Bin Wei*. Metabologenomics analysis reveals antibiotic crypticity of Kutzneria viridogrisea DSM 43850. Journal of Applied Microbiology (2025). (https://doi.org/10.1093/jambio/lxaf114)

Abstract

Aims This study aimed to explore the secondary metabolic potential of Kutzneria viridogrisea DSM 43850 by conducting whole-genome sequencing and utilizing bioinformatics tools to analyze its biosynthetic gene clusters (BGCs). Additionally, the secondary metabolites produced by this strain were investigated under various chemical elicitors using untargeted metabolomics techniques.

Methods and Results The complete genome of Kutzneria viridogrisea DSM 43850 was obtained by re-sequencing, followed by in-depth bioinformatics analysis to assess its secondary metabolic potential. The genome was found to encode a circular 10.2 Mb chromosome, with 4.3% of its functional genes involved in secondary metabolism. The strain harbors 52 BGCs, of which only four are associated with known products. Among these, eight gene clusters were identified as RiPPs (Ribosomally synthesized and post-translationally modified peptides), and the precursor peptide structures of four were predicted, all featuring novel scaffolds. Untargeted metabolomics analysis using LC-MS revealed that the strain could produce a series of novel secondary metabolites when induced with kanamycin and an ebselen derivative.

Conclusions This study highlights the significant secondary metabolic potential of Kutzneria viridogrisea DSM 43850, uncovering several novel BGCs and metabolic products.

10. Tongqing Li, Xueying Liu, Haifeng Qian, Sheyu Zhang, Yu Hou, Yuchao Zhang, Guoyan Luo, Xun Zhu, Yanxin Tao, Mengyang Fan, Hong Wang, Chulin Sha, Ailan Lin, Jingjing Qin, Kedan Gu, Weichang Chen, Ting Fu, Yajun Wang, Yong Wei, Qin Wu & Weihong Tan. Blocker-SELEX: a structure-guided strategy for developing inhibitory aptamers disrupting undruggable transcription factor interactions. Nature Communications, 2024, 15:6751. ( https://doi.org/10.1038/s41467-024-51197-w)

Abstract

Despite the well-established significance of transcription factors (TFs) in pathogenesis, their utilization as pharmacological targets has been limited by the inherent challenges in modulating their protein interactions. The lack of defined small-molecule binding pockets and the nuclear localization of TFs do not favor the use of traditional tools. Aptamers possess large molecular weights, expansive blocking surfaces and efficient cellular internalization, making them compelling tools for modulating TF interactions. Here, we report a structure-guided design strategy called Blocker-SELEX to develop inhibitory aptamers (iAptamers) that selectively block TF interactions. Our approach leads to the discovery of iAptamers that cooperatively disrupt SCAF4/SCAF8-RNAP2 interactions, dysregulating RNAP2-dependent gene expression, which impairs cell proliferation. This approach is further applied to develop iAptamers blocking WDR5-MYC interactions. Overall, our study highlights the potential of iAptamers in disrupting pathogenic TF interactions, implicating their potential utility in studying the biological functions of TF interactions and in nucleic acids drug discovery.

11. Zhehui Cai, Zhe Hu, Xiaojun Yao, Pengyu Liang, Huawei Zhang*. Single-crystal structure, Hirshfeld surface and DFT analyses of chrysomycin A, a marine microbe-derived promising agent for anticancer and antimicrobial therapy. Journal of Molecular Structure, 2025,1322,140488. (https://doi.org/10.1016/j.molstruc.2024.140488) 

Abstract

Chrysomycin A (CA) is an important Streptomyces-derived aromatic polyketide with therapeutic potential for treatment of cancer and bacterial infections. In order to prepare highly pure CA for new drug development, a simple and effective strategy to crystallize CA was firstly developed by the liquid phase diffusion method in this work. The single-crystal structure of CA and its Hirshfeld surface property analyses showed that the asymmetric unit of CA crystal consists of one CA molecule and a water in the orthorhombic space group P212121 and it has π-π interactions between benzene rings. CA crystal stacking is consolidated by three intermolecular hydrogen bonds including carbonyl/keto-C-O⋅⋅⋅H(water), naphthalene-C-O⋅⋅⋅H(water) and glycoside-O H⋅⋅⋅O(water) and van der Waals forces. Furthermore, the HOMO-LUMO energy gap, UV-vis spectral parameters, electrostatic potential, mullliken charge and nonlinear optical properties analyzed in DFT calculations. These results pave a fundamental way for the production of CA using the feasible crystallization approach and the study of molecular mechanisms of action (MoA).

12. Yifan Bai, Tao Luo, Zhehui Cai, Wangjie Zhu, Yuanyuan Liu, Huawei Zhang*. Green and efficient extraction of an anticaner agent N-methylsansalvamide using ultrasound-assisted deep eutectic solvents from mycelia of strain Frusarium sp. R1. Talanta, 2025, 282, 127017. (https://doi.org/10.1016/j.talanta.2024.127017)

Abstract

N-methylsansalvamide (SA), one of cyclic pentadepsipeptides produced by several Fusarium strains, is a promising therapeutic agent for the treatment of cancer disease. In order to make sufficient amount of SA for drug development, a green and efficient extraction process of SA from the mycelia of strain Fusarium sp. R1 using deep eutectic solvent-assisted ultrasound extraction (DES-UAE) was firstly achieved in this work. Solvent screening results indicated that choline chloride-acetic acid (ChCl-Aa) was shown to be the best DES for SA extraction. Through single-factor trials, Plackett-Burman design (PBD) and BoxBehnken design (BBD) experiments, the optimal conditions for DES-UAE with the highest SA yield of 58.2 ± 1.1 mg/g were obtained as follows: ChCl-Aa ratio of 1:2.0 (M/M), water content of 16.4 %, liquid-solid ratio of 37:1 (mL/g), ultrasonic power of 175 W for 47.4 min at 46.3 °C. Compared to conventional extraction approaches, DES-UAE exhibited better SA yield since it caused more serious damage to the surface of mycelia powder on basis of scanning electron microscopy (SEM) analysis. Furthermore, molecular interaction studies suggested that SA has a variety of interactions with ChCl-Aa, including hydrogen and electrovalent bonds as well as van der Waals forces. Finally, the recovery rate of SA reached up to 99.5 % when the ratio of distilled water and DES extracts was 15:1 (V/V). These findings provide the way for large-scale production of SA.

13. Jiapei Chen, Xusheng Duan, Mengyuan Wu, Guishun Bai, Jianwei Chen, Xuanrong Sun, Jean Rodriguez, Damien Bonne*,  Hong Wang* and Xiaoze Bao*. Enantioselective and Diastereodivergent Construction of Oxindole-pyrazolone Conjugates Bearing an Alkenyl Substituted Quaternary Chlorinated Stereogenic Centre. Organic Chemistry Frontiers, 2025. (https://doi.org/10.1039/D5QO00499C)

Abstract

Chlorinated stereogenic carbon centres are important elements both in pharmaceutical reagents and synthetic intermediates. Herein, a novel methodology is reported for the construction of a rarely developed alkenyl substituted quaternary chlorinated stereogenic centre, featured in oxindole and pyrazolone pharmacophores. Remarkably, the configuration of the double bond was switchable via the combination of a suitable base and solvent. In addition, the enantioselective synthesis of Z-type products was achieved with natural quinidine as a catalyst, affording the chlorinated products in excellent yields and stereoselectivities. Preliminary 1H-NMR titration was studied to gain insights into the control of the double bond's configuration. Moreover, the anti-tumour activity against the A549 cell-line of these newly synthesized chemical entities was evaluated, and the product (E)-5ca was revealed to be a promising anti-tumour agent.

14. Yujie Zhao, Qing Gong, and Huawei Zhang*. Engineering of Global Transcriptional Regulators (GTRs) in Aspergillus for Natural Product Discovery. Journal of fungi. 2025, 11(6), 449. (https://doi.org/10.3390/jof11060449)

Abstract

The Aspergillus genus is an important group of filamentous fungi, and the various biological activities of its secondary metabolites (SMs) have great biosynthetic potential. Despite over 4200 SMs having been isolated from Aspergillus spp., their metabolic potential remains unexplored due to the presence of numerous silent biosynthetic gene clusters (BGCs) in their genomes. Fortunately, over the last two decades, the global transcriptional regulator (GTR) engineering strategy has emerged as a powerful tool for activating these cryptic BGCs in order to synthesize previously undiscovered SMs from Aspergillus spp. This review highlights recent advances in fungal GTR engineering techniques, the regulatory mechanisms of GTRs, and current challenges and future perspectives for their application in natural product discovery in the genus Aspergillus.

15. Xiaoze Bao*, Mengyuan Wu, Guishun Bai, Xusheng Duan, Jiangwei Pan, Yang Yang, Zeyu Wang, Xuanrong Sun, Jean Rodriguez, Damien Bonne*, Hong Wang*. Organocatalytic Diastereo- and Enantioselective Synthesis of Chlorinated and Trifluoromethylated Pyrrolidines Featuring a Removable Nitro Group. Organic Letters. 2025, 27, 7908-7913. (https://pubs.acs.org/doi/10.1021/acs.orglett.5c02233)

Abstract

A new concept was reported to use nitro as a removable activating group for the stereoselective construction of chlorinated stereogenic centers. This was proven by the enantioselective (3 + 2) cycloaddition of isatin-derived 1,3-dipoles and chloronitroalkenes, affording a series of spiro-oxindoles featuring four consecutive stereogenic centers including one that is chlorinated.