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Discovery and mechanism verification of first-in-class hydrophobic tagging-based degraders of HBV core protein

Acta Pharmaceutica Sinica B 2025年第4期15卷 2170-2196页

作者： Xu, Shujing Wang, Ya Shi, Dazhou Wang, Shuo Qiao, Lijun Yang, Ge Zhou, Yang Liu, Xinyong Wu, Shuo Li, Yuhuan Zhan, Peng Department of Medicinal Chemistry Key Laboratory of Chemical Biology Ministry of Education School of Pharmaceutical Sciences Shandong University Jinan 250012 China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Beijing Key Laboratory of Antimicrobial Agents NHC Key Laboratory of Biotechnology for Microbial Drugs CAMS Key Laboratory of Antiviral Drug Research Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China

Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure–activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC₅₀ = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC₅₀ = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy–lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles. © 2025 The Author(s)

关键词： Autophagy–lysosome pathway Core protein Degrader Drug design Drug resistance Hepatitis B virus Hydrophobic tagging Mechanism verification

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Advances in development of antiviral strategies against respiratory syncytial virus

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Acta Pharmaceutica Sinica B 2025年第4期15卷 1752-1772页

作者： Yang, Ge Jiang, Guangyu Jiang, Jiandong Li, Yuhuan State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China CAMS Key Laboratory of Antiviral Drug Research Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China Beijing Key Laboratory of Antimicrobial Agents Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China NHC Key Laboratory of Biotechnology for Microbial Drugs Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and young children, as well as an important cause of respiratory tract infections in immunocompromised patients and the elderly, which poses a significant economic and social burden worldwide. In recent years, substantial progress has been made in understanding the structure and function of RSV proteins and the interactions between RSV with host factors which is helpful to the discovery of new therapeutic targets and the development of novel interventions. Although two vaccines and two monoclonal antibodies for RSV prevention have been approved, the antiviral treatment remains an unmet clinical need. In this review, we summarize the structure, protein functional properties, and pathological mechanisms of RSV and the current status of RSV drug development. In addition, remaining challenges and innovative ideas for RSV prevention and treatment have also been highlighted. © 2025 The Authors

关键词： Antivirals Drug development Infection New strategies Respiratory syncytial virus (RSV) Therapeutic targets Viral entry Viral replication

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Long noncoding RNA GAS5 acts as a competitive endogenous RNA to regulate GSK-3β and PTEN expression by sponging miR-23b-3p in Alzheimer's disease

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Neural Regeneration Research 2026年第1期21卷 392-405页

作者： Li Zeng Kaiyue Zhao Jianghong Liu Mimin Liu Zhongdi Cai Ting Sun Zhuorong Li Rui Liu Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Medicinal BiotechnologyPeking Union Medical College and Chinese Academy of Medical SciencesBeijingChina Department of Neurology Xuanwu HospitalCapital Medical UniversityBeijingChina

Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therap

关键词： Alzheimer's disease amyloid-beta peptide accumulation cognitive dysfunction competitive endogenous RNA glycogen synthase kinase 3beta lncRNA growth arrest-specific 5 microRNA-23b-3p neuronal apoptosis phosphatase and tensin homologue deleted on chromosome 10 tau phosphorylation

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The Combination of a Novel Pleuromutilin Derivative and Polymyxin B Nonapeptide: An Example of Converting Pleuromutilin from Gram-Positive-Only to Broad-Spectrum

SSRN

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SSRN 2025年

作者： Luo, Xinyu Fu, Hengjian Zhang, Jie Han, Zunsheng Pan, Weidong Zhang, Wenxuan Xia, Jie Wu, Song State Key Laboratory of Bioactive Substance and Function of Natural Medicines Department of New Drug Research and Development Institute of Materia Medica Chinese Academy of Medical Sciences Peking Union Medical College Beijing100050 China State Key Laboratory of Functions and Applications of Medicinal Plants Guizhou Medical University Guiyang550014 China

To alleviate the difficulties in developing antibiotics for Gram-negative bacteria (GNB), our study focuses on expanding the utility of pleuromutilin derivatives, known as Gram-positive-only antibiotics, in battling against GNB. A series of pleuromutilin derivatives were designed and synthesized, which contributed to a promising compound 15b. It exhibited upgrading activity against both Gram-positive bacteria (GPB) and GNB, as well as promising druglike properties. Combined with the outer membrane disruptor polymyxin B nonapeptide (PMBN, 6), 15b showed further enhanced activities against various GNB, less induced resistance, low impact on polymyxin-related resistance, and in vivo efficacy in Galleria mellonella model. Our results indicate the potential of pleuromutilin derivatives as viable broad-spectrum treatment options. © 2025, The Authors. All rights reserved.

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miR-486-3p Suppresses Osteosarcoma Proliferation and Migration by Targeting the SPRED1-MAPK/ERK Pathway

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Biochemical Genetics 2025年 1-17页

作者： Zhang, Yu Zhou, Yi Zhang, Sen Zhang, Xiaoying Li, Jiaxin Zhan, Xiao-Kai Department of Orthopaedics The First People’s Hospital of Chengdu Sichuan Province Chengdu China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China Department of Gastrointestinal Surgery Lishui Hospital Affiliated of Wenzhou Medical University & Lishui City People’s Hospital Zhejiang Province Lishui China Department of Hematology and Oncology Beijing Chao-Yang Hospital Capital Medical University Beijing 100020 China

Osteosarcoma (OS) is a common malignancy of the bone that originates from stromal cell lines. One of the key cellular pathways extensively studied in OS is the mitogen-activated protein kinase (MAPK) pathway, particularly ERK1/2, whose activation is closely associated with tumor growth and metastasis. MicroRNA (miRNA)-based detection and targeted therapies offer promising new strategies for the treatment of OS. In this study, we investigated the role of miR‑486‑3p in the regulation of the ERK1/2 pathway in OS. We examined the expression level of miR‑486‑3p in the GEO dataset (GSE65071) and clinical samples, and analyzed its regulation of the target gene SPRED1 in OS cells and tumor-bearing mice. Downregulation of miR‑486‑3p was confirmed in OS tissues, with its expression decreasing in line with the progression of clinical stages. Furthermore, the exogenous introduction of a miR-486-3p mimic attenuated the malignant behavior of OS cells, inhibiting their proliferation, migration, and invasion. Bioinformatic analysis revealed that miR‑486‑3p directly targets SPRED1 in OS, leading to alterations in epithelial-to-mesenchymal transition (EMT) markers, including E-cadherin, N-cadherin, and Vimentin. Functional loss- and gain-of-function experiments confirmed that miR‑486‑3p directly targets SPRED1 and inactivates the ERK1/2 pathway in both OS cells and tumor-bearing mice. This review demonstrates that downregulation of miR-486-3p leads to increased SPRED1 expression, which activates the ERK1/2 pathway in OS. Targeting miR-486-3p and SPRED1 could offer potential therapeutic benefits. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.

关键词： ERK1/2 MAPK MiR‑486‑3p Osteosarcoma SPRED1

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Evaluating the Neuroprotective Effects of the Novel Kv2.1 Blocker Zj7923 against Ischemic Stroke In Vitro and In Vivo

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Neuropharmacology 2025年 110537页

作者： Tianjiao Yang Weiping Wang Zhuo Li Jie Cai Nan Feng Shaofeng Xu Ling Wang Xiaoliang Wang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

The voltage-dependent potassium channel Kv2.1 correlates closely to the regulation of neuronal excitability and cellular apoptosis. Ischemia or oxidative treatment were known to stimulate the surge of Kv2.1-mediated current to activate neuronal apoptosis pathways, while inhibiting excessive Kv2.1 K + current efflux could reduce neuronal apoptosis and exhibit neuroprotective effects. Here, we found a novel Kv2.1 selective blocker Zj7923 and investigated whether it produces neuroprotective function after ischemic stroke animal model. We demonstrate that Zj7923 potently inhibits Kv2.1 current with an IC 50 of 0.12 μM. Zj7923 had no obvious effect on the activation process of Kv2.1 channels, but could significantly accelerate the inactivation process of Kv2.1 channels. The mutations at Y380 and K356 in the outer vestibule of Kv2.1 channels weakened the inhibitory effect of Zj7923, and the IC 50 value of Zj7923 on the mutation channels increased to 3.66 μM and 3.20 μM, respectively, indicating that the compound may act on the above two positions. Zj7923 could increase the spontaneous firing rate of normal hippocampal pyramidal neurons and ameliorate OGD-induced impairment of neuronal excitability. Kv2.1 channel inhibition by Zj7923 provides protection against DTDP-induced apoptosis and its mechanism might be related to the modulation of the expression of apoptosis-related proteins, such as Bcl-2, Bax and cleaved caspase-3 proteins. In vivo pharmacodynamics evaluation, intravenous administration of Zj7923 in rats following transient middle cerebral artery occlusion significantly reduced infarct volume and improved neurological deficits. Our results indicate that Zj7923 exerts a neuronal protection from cerebral ischemia in vitro and in vivo by inhibiting Kv2.1 current and validate the potential value of developing drugs targeting Kv2.1 for ischemic stroke.

关键词： Kv2.1 apoptosis cerebral ischemia neuronal excitability neuroprotection potassium channel blocker

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A concise total synthesis of monoterpenoid indole alkaloid (-)-voacafricine A

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Chinese Chemical Letters 2025年

作者： Xuan Pan Tao Sheng Zhanzhu Liu State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Peking Union Medical College and Chinese Academy of Medical Sciences Beijing 100050 China

A concise total synthesis of novel monoterpenoid indole alkaloid (-)-voacafricine A is described, which proceeded in 14 longest linear steps and 5.2% overall yield. key transformations comprised of (a) an organocatalytically asymmetric Pictet-Spengler cyclization/lactamization cascade reaction generating the key tetracyclic lactam skeleton; (b) asymmetric α -alkylation of carbonyl group induced by Evans’ chiral auxiliary with excellent diastereoselectivity; (c) a highly efficient one-pot desulfurization/hydrogenation/debenzylation transformation using Raney Ni under hydrogen atmosphere; as well as (d) an intramolecular Vorbürggen reaction constructing the quaternary ammonium motif and the final cagelike skeleton.

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Potassium 2-(1-hydroxypentyl)-benzoate improves depressive-like behaviors in rat model

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Acta Pharmaceutica Sinica B 2018年第6期8卷 881-888页

作者： Hao Ma Weiping Wang Shaofeng Xu Ling Wang Xiaoliang Wang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College

Potassium 2-(1-hydroxypentyl)-benzoate(PHPB) is a novel drug candidate for acute ischemic stroke. PHPB has been also shown to be beneficial for some neurodegenerative diseases. In this study, we demonstrated that PHPB improved depressive-like behaviors induced by chronic unpredictable mild stress(CUMS) in rats. Male SD rats were subjected to the stress for five weeks. PHPB(30 and 100 mg/kg) or fluoxetine(FLX 10 mg/kg, as positive control) was administered orally from the third week in CUMS procedure. The behavioral tests were applied and then the biochemical studies were carried out. PHPB or FLX treatment rescued the behavioral deficiency in CUMS-exposed rats. Meanwhile, PHPB normalized the enhanced level of serum corticosterone, improved hippocampal and serum BDNF levels, as well as p-CREB level in hippocampus. In addition, PHPB could reverse the reduced level of extracellular 5-HT and its metabolite 5-HIAA in prefrontal cortex(PFC) of depressed rats. In summary, our results showed that PHPB improved depression-like behaviors in CUMS-exposed rats. The mechanisms might relate to the reverse of neurotrophic disturbance in the brain, reducing excessive HPA axis response and facilitating the release of 5-HT.

关键词： PHPB CUMS Antidepressant BDNF HPA axis 5-HT

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Parishin C's prevention of Aβ_(1–42)-induced inhibition of long-term potentiation is related to NMDA receptors

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Acta Pharmaceutica Sinica B 2016年第3期6卷 189-197页

作者： Zhihui Liu Weiping Wang Nan Feng Ling Wang Jiangong Shi Xiaoliang Wang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical College

The rhizome of Gastrodia elata(GE), a herb medicine, has been used for treatment of neuronal disorders in Eastern Asia for hundreds of years. Parishin C is a major ingredient of GE. In this study, the i.c.v. injection of soluble Aβ1–42oligomers model of LTP injury was used. We investigated the effects of parishin C on the improvement of LTP in soluble Aβ1–42oligomer–injected rats and the underlying electrophysiological mechanisms. Parishin C(i.p. or i.c.v.) significantly ameliorated LTP impairment induced by i.c.v. injection of soluble Aβ1–42oligomers. In cultured hippocampal neurons,soluble Aβ1–42oligomers significantly inhibited NMDAR currents while not affecting AMPAR currents and voltage-dependent currents. Pretreatment with parishin C protected NMDA receptor currents from the damage induced by Aβ. In summary, parishin C improved LTP deficits induced by soluble Aβ1–42oligomers. The protection by parishin C against Aβ-induced LTP damage might be related to NMDA receptors.

关键词： Parishin C Long-term potentiation Neuroprotection NMDA receptors Ion channels

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Conversion and pharmacokinetics profiles of a novel pro-drug of 3-n-butylphthalide, potassium 2-(1-hydroxypentyl)-benzoate, in rats and dogs

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中国药理学报（英文版） 2018年第2期39卷 275-285页

作者： Jiang LI Shao-feng XU Ying PENG Nan FENG Ling WANG Xiao-liang WANG State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China

Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) is a novel pro-drug of 3-n-butylphthalide (dl-NBP) that is used to treat ischemic ***,dl-PHPB is in phase Ⅱ-Ⅲ clinical trials in *** this study,we investigated the conversion and pharmacokinetics profiles of dl-PHPB in vitro and in *** conversion of dl-PHPB to dl-NBP was pH-and calcium-dependent,and paraoxonase was identified as a major enzyme for the conversion in rat *** pharmacokinetics,tissue distribution and excretion of dl-PHPB were studied and compared with equal-molar doses of dl-NBP in rats and *** in vivo studies showed that dl-PHPB could be quickly and completely converted to *** plasma concentration-time course of converted dl-NBP after intravenous dl-PHPB administration was nearly the same as that after equal-molar *** Cmax and AUC of dl-NBP after oral dl-PHPB administration in rats and dogs were higher by 60％ and 170％,respectively,than those after oral dl-NBP *** of the tissue distribution of dl-PHPB revealed that converted dl-NBP was primarily distributed in fat,the brain and the *** the brain,the levels of dl-NBP were relatively higher after dl-PHPB treatment by orally than after treatment with equal-molar *** 3％-4％ of dl-NBP was excreted within 72 h after dosing with dl-PHPB or dl-NBP,but no dl-PHPB was detected in urine or feces *** results demonstrate that the conversion of dl-PHPB is fast after oral or intravenous ***,the bioavailability of dl-PHPB was obviously better than that of dl-NBP.

关键词： potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) pro-drug 3-n-butylphthalide (dl-NBP) ischemic stroke pharmacokinetics bioavailability

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