Acta Pharmaceutica Sinica. B最新文献_第3页

A proximity-induced chimera platform for targeted protein arginine methylation

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.049

Yanlin Jian , Tianyang Zhou , Chendong Guo , Yibo Gao, Chen Yao, Zixi Wang, Xuehan Jiang, Ke Wang, Jian Ma, Yang Gao, Yizeng Fan, Jing Liu, Bohan Ma, Lei Li

{"title":"A proximity-induced chimera platform for targeted protein arginine methylation","authors":"Yanlin Jian , Tianyang Zhou , Chendong Guo , Yibo Gao, Chen Yao, Zixi Wang, Xuehan Jiang, Ke Wang, Jian Ma, Yang Gao, Yizeng Fan, Jing Liu, Bohan Ma, Lei Li","doi":"10.1016/j.apsb.2025.03.049","DOIUrl":"10.1016/j.apsb.2025.03.049","url":null,"abstract":"<div><div>Arginine methylation is a critical post-translational modification that plays multifaceted biological functions. However, the manipulation of protein arginine methylation largely depends on genetic or pharmaceutic inhibition of the regulatory enzymes, protein arginine methyltransferases (PRMTs), or non-methylation substitution of corresponding arginine residue to lysine or alanine of protein of interest (POI), which inevitably affects other substrates, or disrupts the structure of POI. Thus, it urges an approach to specifically modulate the arginine methylation of a POI under physiological conditions. To this end, we report the discovery of a methylation tagging system (MeTAG), that enables targeted modification of protein arginine methylation. Through bridging the methyltransferase PRMT5 proximity to a POI, MeTAG facilitates the arginine methylation of POIs, including known arginine methylated proteins, androgen receptor (AR) and protein kinase B (AKT), as well as a neo-substrate E1A binding protein (p300), in a reversible and PRMT5-dependent manner. Moreover, MeTAG can regulate downstream signaling in a methylation dependent manner, leading to downregulation of <em>PSMA</em> mRNA level and activation of AKT. Therefore, MeTAG represents a feasible approach to modulate protein methylation and thereby perturbs protein function in biological and therapeutic contexts.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2625-2639"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Anti-SARS-CoV-2 prodrug ATV006 has broad-spectrum antiviral activity against human and animal coronaviruses

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.02.028

Tiefeng Xu , Kun Li , Siyao Huang , Konstantin I. Ivanov , Sidi Yang , Yanxi Ji , Hanwei Zhang , Wenbin Wu , Ye He , Qiang Zeng , Feng Cong , Qifan Zhou , Yingjun Li , Jian Pan , Jincun Zhao , Chunmei Li , Xumu Zhang , Liu Cao , Deyin Guo

{"title":"Anti-SARS-CoV-2 prodrug ATV006 has broad-spectrum antiviral activity against human and animal coronaviruses","authors":"Tiefeng Xu , Kun Li , Siyao Huang , Konstantin I. Ivanov , Sidi Yang , Yanxi Ji , Hanwei Zhang , Wenbin Wu , Ye He , Qiang Zeng , Feng Cong , Qifan Zhou , Yingjun Li , Jian Pan , Jincun Zhao , Chunmei Li , Xumu Zhang , Liu Cao , Deyin Guo","doi":"10.1016/j.apsb.2025.02.028","DOIUrl":"10.1016/j.apsb.2025.02.028","url":null,"abstract":"<div><div>Coronavirus-related diseases pose a significant challenge to the global health system. Given the diversity of coronaviruses and the unpredictable nature of disease outbreaks, the traditional “one bug, one drug” paradigm struggles to address the growing number of emerging crises. Therefore, there is an urgent need for therapeutic agents with broad-spectrum anti-coronavirus activity. Here, we provide evidence that ATV006, an anti-SARS-CoV-2 nucleoside analog targeting RNA-dependent RNA polymerase (RdRp), has broad antiviral activity against human and animal coronaviruses. Using mouse hepatitis virus (MHV) and human coronavirus NL63 (HCoV-NL63) as a model, we show that ATV006 has potent prophylactic and therapeutic activity against murine coronavirus infection <em>in vivo</em>. Remarkably, ATV006 successfully inhibits viral replication in mice even when administered 96 h after infection. Due to its oral bioavailability and potency against multiple coronaviruses, ATV006 has the potential to become a useful antiviral agent against SARS-CoV-2 and other circulating and emerging coronaviruses in humans and animals.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2498-2510"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deubiquitinase USP13 alleviates doxorubicin-induced cardiotoxicity through promoting the autophagy-mediated degradation of STING

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.051

Liming Lin , Jibo Han , Diyun Xu , Zimin Fang , Bozhi Ye , Jinfu Qian , Xue Han , Julian Min , Xiaohong Long , Gaojun Wu , Guang Liang

{"title":"Deubiquitinase USP13 alleviates doxorubicin-induced cardiotoxicity through promoting the autophagy-mediated degradation of STING","authors":"Liming Lin , Jibo Han , Diyun Xu , Zimin Fang , Bozhi Ye , Jinfu Qian , Xue Han , Julian Min , Xiaohong Long , Gaojun Wu , Guang Liang","doi":"10.1016/j.apsb.2025.03.051","DOIUrl":"10.1016/j.apsb.2025.03.051","url":null,"abstract":"<div><div>Doxorubicin (Dox) is an anthracycline drug widely applied in various malignancies. However, the fatal cardiotoxicity induced by Dox limits its clinical application. Post-transcriptional protein modification <em>via</em> ubiquitination/deubiquitination in cardiomyocytes mediates the pathophysiological process in Dox-induced cardiotoxicity (DIC). In this study, we aimed to clarify the regulatory role and mechanism of a deubiquitinating enzyme, ubiquitin-specific peptidase 13 (USP13), in DIC. RNA-seq analysis and experimental examinations identified that cardiomyocyte-derived USP13 positively correlated with DIC. Mice with cardiac-specific deletion of USP13 were subjected to Dox modeling. Adeno-associated virus serotype 9 (AAV9) carrying <em>cTNT</em> promoter was constructed to overexpress USP13 in mouse heart tissues. Cardiomyocyte-specific knockout of USP13 exacerbated DIC, while its overexpression mitigated DIC in mice. Mechanistically, USP13 deubiquitinates the stimulator of interferon genes (STING) and promotes the autolysosome-related degradation of STING, subsequently alleviating cardiomyocyte inflammation and death. Our study suggests that USP13 serves a cardioprotective role in DIC and indicates USP13 as a potential therapeutic target for DIC treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2545-2558"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Precise nanoscale fabrication technologies, the “last mile” of medicinal development

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.040

Ye Bi , Sensen Xie , Ziwei Li , Shiyan Dong , Lesheng Teng

引用次数: 0

Sulfafurazole dimers potentiate chemo-immunotherapy of low immunogenic breast cancer by preventing the PD-L1 exosomes secretion

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.007

Zheng Wang, Ronghui Yin, Lin Zhang, Shiyu Li, Zhanwei Zhou, Minjie Sun

{"title":"Sulfafurazole dimers potentiate chemo-immunotherapy of low immunogenic breast cancer by preventing the PD-L1 exosomes secretion","authors":"Zheng Wang, Ronghui Yin, Lin Zhang, Shiyu Li, Zhanwei Zhou, Minjie Sun","doi":"10.1016/j.apsb.2025.03.007","DOIUrl":"10.1016/j.apsb.2025.03.007","url":null,"abstract":"<div><div>The <em>α</em>PD-L1 antibody-based immune checkpoint blockade therapy is still limited by the poor clinical response rate as it is mainly utilized to block surface PD-L1 on tumor cells while ignoring abundant PD-L1 exosomes secreted in the environment, causing tumor immune evasion. Here, we proposed an exosome biogenesis inhibition strategy to suppress tumor exosomes secretion from the source, reducing the inhibitory effect on T cells and enhancing chemo-immunotherapy efficacy. We developed sulfafurazole homodimers (SAS) with disulfide linkages, effectively releasing the drug in response to glutathione (GSH) and inhibiting 4T1 tumor-derived exosomes secretion. Subsequently, gemcitabine (Gem) was encapsulated to induce immunogenic cell death (ICD). Consequently, Gem@SAS inhibited the secretion of tumor exosomes by more than 70%, increased proliferation and granzyme B secretion ability of T cells by more than 2 times, and showed superior efficacy in breast cancer treatment as well as lung metastasis of breast cancer.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2673-2686"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapy

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.014

Muhammad Hamza , Shuai Wang , Hao Wu , Jiayi Sun , Yang Du , Chuting Zeng , Yike Liu , Kun Li , Xili Zhu , Huiying Liu , Lin Chen , Motao Zhu

{"title":"Targeting copper homeostasis: Akkermansia-derived OMVs co-deliver Atox1 siRNA and elesclomol for cancer therapy","authors":"Muhammad Hamza , Shuai Wang , Hao Wu , Jiayi Sun , Yang Du , Chuting Zeng , Yike Liu , Kun Li , Xili Zhu , Huiying Liu , Lin Chen , Motao Zhu","doi":"10.1016/j.apsb.2025.03.014","DOIUrl":"10.1016/j.apsb.2025.03.014","url":null,"abstract":"<div><div>Cuproptosis, a recently identified form of regulated cell death triggered by excess intracellular copper, has emerged as a promising cytotoxic strategy for cancer therapy. However, the therapeutic efficacy of copper ionophores such as elesclomol (ES) is often hindered by cellular copper homeostasis mechanisms that limit copper influx and cuproptosis induction. To address this challenge, we developed a nanoagent utilizing outer membrane vesicle (OMV) derived from <em>Akkermansia muciniphila</em> (<em>Akk</em>) for co-delivery of antioxidant 1 copper chaperone (<em>Atox1</em>)-targeting siRNA and ES (siAtox1/ES@OMV) to tumors. <em>In vitro</em>, we demonstrated that <em>Atox1</em> knockdown <em>via</em> siRNA significantly disrupted copper export mechanisms, resulting in elevated intracellular copper levels. Simultaneously, ES facilitated efficient copper influx and mitochondrial transport, leading to Fe–S cluster depletion, increased proteotoxic stress, and robust cuproptosis. <em>In vivo</em>, siAtox1/ES@OMV achieved targeted tumor delivery and induced pronounced cuproptosis. Furthermore, leveraging the immunomodulatory properties of OMVs, siAtox1/ES@OMV promoted T-cell infiltration and the activation of tumor-reactive cytotoxic T cells, enhancing tumor immune responses. The combination of siAtox1/ES-induced cuproptosis and immunogenic cell death synergistically suppressed tumor growth in both subcutaneous breast cancer and orthotopic rectal cancer mouse models. This study highlights the potential of integrating copper homeostasis disruption with a copper ionophore using an immunomodulatory OMV-based vector, offering a promising combinatorial strategy for cancer therapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2640-2654"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design and functional characterization of a tetravalent NK cell-engaging bispecific antibody with enhanced half-life for CD30+ lymphoma

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.012

Caizhi Zhao , Liping Xie , Ming-Wei Wang , Youjia Hu

引用次数: 0

Innovative discovery and mechanistic validation of HyT-PD ligands for selective CDK9-targeted protein degradation HyT-PD配体选择性cdk9靶向蛋白降解的创新发现和机制验证

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.04.023

Yizhan Zhai, Jianfeng Cai

引用次数: 0

The neuroscience of cancer: Focus on neuropeptidergic systems

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.03.025

Zikai Dong , Yongfei Wang , Weilin Jin

{"title":"The neuroscience of cancer: Focus on neuropeptidergic systems","authors":"Zikai Dong , Yongfei Wang , Weilin Jin","doi":"10.1016/j.apsb.2025.03.025","DOIUrl":"10.1016/j.apsb.2025.03.025","url":null,"abstract":"<div><div>Tumors are complex, highly heterogeneous diseases that place an enormous burden on the world's healthcare systems. Updating understanding of tumor initiation and progression is critical and the current breakthrough lies in cancer neuroscience, which focuses on the crosstalk between neural components and tumors. Neuropeptides are a class of highly potent peptides, that perform the physiological functions of neurotransmitters, neuromodulators, and endocrine hormones. Currently, many studies have shown that many cellular components of the tumor microenvironment express neuropeptides and their receptors and that neuropeptides may play an important role in their cellular communication. In addition, neuropeptides and their receptors affect cancer hallmarks such as proliferation, invasion and metastasis, angiogenesis, immune escape, metabolic reprogramming, and others. More importantly, neuropeptides may also affect some tumor comorbidities such as insomnia, depression, anorexia, cancer pain, and others. Targeting neuropeptides in combination with new therapeutic strategies may significantly advance anti-tumor therapy, not only for treating the tumor itself but also for improving the patient's quality of life.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 5","pages":"Pages 2323-2350"},"PeriodicalIF":14.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143943522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Extrachromosomal DNA as a carrier of extra copies of oncogenes for heterogeneity and malignancy of glioma

IF 14.7 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2025-05-01 DOI: 10.1016/j.apsb.2025.02.001

Lin-jian Wang , Jianping Ye

引用次数: 0