Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.06.026
Cell death is a central process for organismal health. Pyroptosis, namely pyroptotic cell death, is recognized as a critical type that disrupts membrane and triggers pro-inflammatory cytokine secretion via gasdermins, providing a robust form of cytolysis. Meanwhile, along with the thorough research, a great deal of evidence has demonstrated the dual effects of pyroptosis in host defense and inflammatory diseases. More importantly, the recent identification of abundant gasdermin-like proteins in bacteria and fungi suggests an ancient origin of pyroptosis-based regulated cell death in the life evolution. In this review, we bring a general overview of pyroptosis pathways focusing on gasdermin structural biology, regulatory mechanisms, and recent progress in induction and inhibition strategies for disease treatment. We look forward to providing an insightful perspective for readers to comprehend the frame and challenges of the pyroptosis field, and to accelerating its clinical application.
{"title":"Pyroptosis: Induction and inhibition strategies for immunotherapy of diseases","authors":"","doi":"10.1016/j.apsb.2024.06.026","DOIUrl":"10.1016/j.apsb.2024.06.026","url":null,"abstract":"<div><div>Cell death is a central process for organismal health. Pyroptosis, namely pyroptotic cell death, is recognized as a critical type that disrupts membrane and triggers pro-inflammatory cytokine secretion <em>via</em> gasdermins, providing a robust form of cytolysis. Meanwhile, along with the thorough research, a great deal of evidence has demonstrated the dual effects of pyroptosis in host defense and inflammatory diseases. More importantly, the recent identification of abundant gasdermin-like proteins in bacteria and fungi suggests an ancient origin of pyroptosis-based regulated cell death in the life evolution. In this review, we bring a general overview of pyroptosis pathways focusing on gasdermin structural biology, regulatory mechanisms, and recent progress in induction and inhibition strategies for disease treatment. We look forward to providing an insightful perspective for readers to comprehend the frame and challenges of the pyroptosis field, and to accelerating its clinical application.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4195-4227"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141552695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.07.005
Qinghua Wang , Tingting Du , Zhihui Zhang , Qingyang Zhang , Jie Zhang , Wenbin Li , Jian-Dong Jiang , Xiaoguang Chen , Hai-Yu Hu
Chlorogenic acid (CGA) is a natural product that effectively inhibits tumor growth, demonstrated in many preclinical models, and phase II clinical trials for patients with glioma. However, its direct proteomic targets and anticancer molecular mechanisms remain unknown. Herein, we developed a novel bi-functional photo-affinity probe PAL/CGA and discovered mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) was one of the main target proteins of CGA by using affinity-based protein profiling (AfBPP) chemical proteomic approach. We performed in-depth studies on ACAT1/CGA interactions via multiple assays including SPR, ITC, and cryo-EM. Importantly, we demonstrated that CGA impaired cancer cell proliferation by inhibiting the phosphorylation of tetrameric ACAT1 on Y407 residue through a novel mode of action in vitro and in vivo. Our study highlights the use of AfBPP platforms in uncovering unique druggable modalities accessed by natural products. And identifying the molecular target of CGA sheds light on the future clinical application of CGA for cancer therapy.
{"title":"Target fishing and mechanistic insights of the natural anticancer drug candidate chlorogenic acid","authors":"Qinghua Wang , Tingting Du , Zhihui Zhang , Qingyang Zhang , Jie Zhang , Wenbin Li , Jian-Dong Jiang , Xiaoguang Chen , Hai-Yu Hu","doi":"10.1016/j.apsb.2024.07.005","DOIUrl":"10.1016/j.apsb.2024.07.005","url":null,"abstract":"<div><div>Chlorogenic acid (CGA) is a natural product that effectively inhibits tumor growth, demonstrated in many preclinical models, and phase II clinical trials for patients with glioma. However, its direct proteomic targets and anticancer molecular mechanisms remain unknown. Herein, we developed a novel bi-functional photo-affinity probe PAL/CGA and discovered mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) was one of the main target proteins of CGA by using affinity-based protein profiling (AfBPP) chemical proteomic approach. We performed in-depth studies on ACAT1/CGA interactions <em>via</em> multiple assays including SPR, ITC, and cryo-EM. Importantly, we demonstrated that CGA impaired cancer cell proliferation by inhibiting the phosphorylation of tetrameric ACAT1 on Y407 residue through a novel mode of action <em>in vitro</em> and <em>in vivo</em>. Our study highlights the use of AfBPP platforms in uncovering unique druggable modalities accessed by natural products. And identifying the molecular target of CGA sheds light on the future clinical application of CGA for cancer therapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4431-4442"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141612757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.04.007
Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for the disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected by a linker. The linker plays a pivotal role in determining PROTAC's biodegradative efficacy. Advanced and rationally designed functional linkers for PROTAC are under development. Nonetheless, the correlation between linker characteristics and PROTAC efficacy remains under-investigated. Consequently, this study will present a multidisciplinary analysis of PROTAC linkers and their impact on efficacy, thereby guiding the rational design of linkers. We will primarily discuss the structural types and characteristics of PROTAC linkers, and the optimization strategies used for their rational design. Furthermore, we will discuss how factors like linker length, group type, flexibility, and linkage site affect the biodegradation efficiency of PROTACs. We believe that this work will contribute towards the advancement of rational linker design in the PROTAC research area.
{"title":"Characteristic roadmap of linker governs the rational design of PROTACs","authors":"","doi":"10.1016/j.apsb.2024.04.007","DOIUrl":"10.1016/j.apsb.2024.04.007","url":null,"abstract":"<div><div>Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for the disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected by a linker. The linker plays a pivotal role in determining PROTAC's biodegradative efficacy. Advanced and rationally designed functional linkers for PROTAC are under development. Nonetheless, the correlation between linker characteristics and PROTAC efficacy remains under-investigated. Consequently, this study will present a multidisciplinary analysis of PROTAC linkers and their impact on efficacy, thereby guiding the rational design of linkers. We will primarily discuss the structural types and characteristics of PROTAC linkers, and the optimization strategies used for their rational design. Furthermore, we will discuss how factors like linker length, group type, flexibility, and linkage site affect the biodegradation efficiency of PROTACs. We believe that this work will contribute towards the advancement of rational linker design in the PROTAC research area.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4266-4295"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140613731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.06.008
Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis, but its regulatory mechanism remains unclear. As a member of purinoceptors, P2Y6R mainly distributed in macrophages was significantly up-expressed in skin lesions from patients with psoriasis in the present study. Here, the severity of psoriasis was alleviated in imiquimod-treated mice with macrophages conditional knockout of P2Y6R, while the cell-chat algorithm showed there was a correlation between macrophage P2Y6R and Th1 cells mediated by IL-27. Mechanistically, P2Y6R enhanced PLCβ/p-PKC/MAPK activation to induce IL-27 release dependently, which subsequently regulated the differentiation of Th1 cells, leading to erythematous and scaly plaques of psoriasis. Interestingly, we developed a novel P2Y6R inhibitor FS-6, which bonds with the ARG266 side chain of P2Y6R, exhibited remarkable anti-psoriasis effects targeting P2Y6R. Our study provides insights into the role of P2Y6R in the pathogenesis of psoriasis and suggests its potential as a target for the development of therapeutic interventions. A novel P2Y6R inhibitor FS-6 could be developed as an anti-psoriasis drug candidate for the clinic.
{"title":"Macrophage P2Y6R activation aggravates psoriatic inflammation through IL-27-mediated Th1 responses","authors":"","doi":"10.1016/j.apsb.2024.06.008","DOIUrl":"10.1016/j.apsb.2024.06.008","url":null,"abstract":"<div><div>Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis, but its regulatory mechanism remains unclear. As a member of purinoceptors, P2Y<sub>6</sub>R mainly distributed in macrophages was significantly up-expressed in skin lesions from patients with psoriasis in the present study. Here, the severity of psoriasis was alleviated in imiquimod-treated mice with macrophages conditional knockout of P2Y<sub>6</sub>R, while the cell-chat algorithm showed there was a correlation between macrophage P2Y<sub>6</sub>R and Th1 cells mediated by IL-27. Mechanistically, P2Y<sub>6</sub>R enhanced PLC<sub><em>β</em></sub>/p-PKC/MAPK activation to induce IL-27 release dependently, which subsequently regulated the differentiation of Th1 cells, leading to erythematous and scaly plaques of psoriasis. Interestingly, we developed a novel P2Y<sub>6</sub>R inhibitor FS-6, which bonds with the ARG266 side chain of P2Y<sub>6</sub>R, exhibited remarkable anti-psoriasis effects targeting P2Y<sub>6</sub>R. Our study provides insights into the role of P2Y<sub>6</sub>R in the pathogenesis of psoriasis and suggests its potential as a target for the development of therapeutic interventions. A novel P2Y<sub>6</sub>R inhibitor FS-6 could be developed as an anti-psoriasis drug candidate for the clinic.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4360-4377"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141500635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.06.006
Dandan Wan , Ziyi Bai , Yu Zhang , Li Chen , Haiying Que , Tianxia Lan , Weiqi Hong , Jiayu Huang , Cai He , Yuquan Wei , Qiang Pu , Xiawei Wei
Toll-like receptor (TLR) agonists, as promising adjuvants and immunotherapeutic agents, have the potential to enhance immune responses and modulate antigen-dependent T-cell immune memory through activation of distinct signaling pathways. However, their clinical application is hindered by uncontrolled systemic inflammatory reactions. Therefore, it is imperative to create a vaccine adjuvant for TLR receptors that ensures both safety and efficacy. In this study, we designed lymph node-targeted cholesterolized TLR7 agonist cationic liposomes (1V209-Cho-Lip+) to mitigate undesired side effects. Co-delivery of the model antigen OVA and cholesterolized TLR7 agonist facilitated DC maturation through TLR activation while ensuring optimal presentation of the antigen to CD8+ T cells. The main aim of the present study is to evaluate the adjuvant effectiveness of 1V209-Cho-Lip+ in tumor vaccines. Following immunization with 1V209-Cho-Lip++OVA, we observed a pronounced "depot effect" and enhanced trafficking to secondary lymphoid organs. Prophylactic vaccination with 1V209-Cho-Lip++OVA significantly delays tumor development, prolongs mouse survival, and establishes durable immunity against tumor recurrence. Additionally, 1V209-Cho-Lip++OVA, while used therapeutic tumor vaccine, has demonstrated its efficacy in inhibiting tumor progression, and when combined with anti-PD-1, it further enhances antitumor effects. Therefore, the co-delivery of antigen and lymph node-targeted cholesterolized TLR7 agonist shows great promise as a cancer vaccine.
Toll 样受体（TLR）激动剂是一种很有前景的佐剂和免疫治疗剂，有可能通过激活不同的信号通路来增强免疫反应和调节抗原依赖性 T 细胞免疫记忆。然而，它们在临床上的应用却受到不受控制的全身性炎症反应的阻碍。因此，当务之急是为 TLR 受体创造一种既安全又有效的疫苗佐剂。在本研究中，我们设计了淋巴结靶向胆固醇化 TLR7 激动剂阳离子脂质体（1V209-Cho-Lip），以减轻不良副作用。模型抗原 OVA 和胆固醇化 TLR7 激动剂的联合给药有助于通过 TLR 激活促进 DC 成熟，同时确保抗原以最佳方式呈现给 CD8 T 细胞。本研究的主要目的是评估 1V209-Cho-Lip 在肿瘤疫苗中的佐剂效果。在使用 1V209-Cho-Lip+OVA 进行免疫接种后，我们观察到了明显的 "储藏效应 "和向次级淋巴器官的迁移增强。预防性接种 1V209-Cho-Lip+OVA 能显著延缓肿瘤的发展，延长小鼠的存活时间，并建立起防止肿瘤复发的持久免疫力。此外，1V209-Cho-Lip+OVA 作为治疗性肿瘤疫苗，在抑制肿瘤进展方面的疗效已得到证实，与抗-PD-1 结合使用时，可进一步增强抗肿瘤效果。因此，将抗原和淋巴结靶向胆固醇化 TLR7 激动剂联合递送作为癌症疫苗大有可为。
{"title":"Simultaneous enhancement of cellular and humoral immunity by the lymph node-targeted cholesterolized TLR7 agonist liposomes","authors":"Dandan Wan , Ziyi Bai , Yu Zhang , Li Chen , Haiying Que , Tianxia Lan , Weiqi Hong , Jiayu Huang , Cai He , Yuquan Wei , Qiang Pu , Xiawei Wei","doi":"10.1016/j.apsb.2024.06.006","DOIUrl":"10.1016/j.apsb.2024.06.006","url":null,"abstract":"<div><div>Toll-like receptor (TLR) agonists, as promising adjuvants and immunotherapeutic agents, have the potential to enhance immune responses and modulate antigen-dependent T-cell immune memory through activation of distinct signaling pathways. However, their clinical application is hindered by uncontrolled systemic inflammatory reactions. Therefore, it is imperative to create a vaccine adjuvant for TLR receptors that ensures both safety and efficacy. In this study, we designed lymph node-targeted cholesterolized TLR7 agonist cationic liposomes (1V209-Cho-Lip<sup>+</sup>) to mitigate undesired side effects. Co-delivery of the model antigen OVA and cholesterolized TLR7 agonist facilitated DC maturation through TLR activation while ensuring optimal presentation of the antigen to CD8<sup>+</sup> T cells. The main aim of the present study is to evaluate the adjuvant effectiveness of 1V209-Cho-Lip<sup>+</sup> in tumor vaccines. Following immunization with 1V209-Cho-Lip<sup>+</sup>+OVA, we observed a pronounced \"depot effect\" and enhanced trafficking to secondary lymphoid organs. Prophylactic vaccination with 1V209-Cho-Lip<sup>+</sup>+OVA significantly delays tumor development, prolongs mouse survival, and establishes durable immunity against tumor recurrence. Additionally, 1V209-Cho-Lip<sup>+</sup>+OVA, while used therapeutic tumor vaccine, has demonstrated its efficacy in inhibiting tumor progression, and when combined with anti-PD-1, it further enhances antitumor effects. Therefore, the co-delivery of antigen and lymph node-targeted cholesterolized TLR7 agonist shows great promise as a cancer vaccine.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4577-4590"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.05.024
Ototoxicity and nephrotoxicity are the most prevalent side effects of aminoglycoside antibiotics (gentamicin, amikacin, neomycin) and platinum anti-tumor drugs (cisplatin, carboplatin). The inner ear and kidney share similarities in drug deposition and toxicity, but the underlying pathophysiological mechanisms remain unclear. Investigating the shared mechanisms and metabolic alterations in these distinct organs will provide valuable insights for clinical therapy. A strong correlation has been identified between the spatiotemporal accumulation patterns of neomycin and the specific occurrence of lipid metabolism disorders in these two organs. The primary allocation of neomycin to mitochondria results in a notable escalation in the accumulation of lipid droplets (LDs) and more interactions between mitochondria and LDs, leading to a sequence of disturbances in lipid metabolism, such as increased lipid ROS and the blocked transfer of fatty acids from LDs to mitochondria. PGC-1α deficiency worsens the neomycin-induced disorders in lipid metabolism and intensifies the pathological interactions between mitochondria and LDs, as indicated by the exacerbated disturbance of dynamic LD turnover, increased level of oxidized lipids and decreased use of fatty acids. This investigation provides a fresh perspective on the lipid metabolic dysfunction related to mitochondria–LD interactions in drug-induced ototoxicity and nephrotoxicity, potentially providing novel avenues for intervention strategies.
{"title":"PGC-1α-mediated imbalance of mitochondria-lipid droplet homeostasis in neomycin-induced ototoxicity and nephrotoxicity","authors":"","doi":"10.1016/j.apsb.2024.05.024","DOIUrl":"10.1016/j.apsb.2024.05.024","url":null,"abstract":"<div><div>Ototoxicity and nephrotoxicity are the most prevalent side effects of aminoglycoside antibiotics (gentamicin, amikacin, neomycin) and platinum anti-tumor drugs (cisplatin, carboplatin). The inner ear and kidney share similarities in drug deposition and toxicity, but the underlying pathophysiological mechanisms remain unclear. Investigating the shared mechanisms and metabolic alterations in these distinct organs will provide valuable insights for clinical therapy. A strong correlation has been identified between the spatiotemporal accumulation patterns of neomycin and the specific occurrence of lipid metabolism disorders in these two organs. The primary allocation of neomycin to mitochondria results in a notable escalation in the accumulation of lipid droplets (LDs) and more interactions between mitochondria and LDs, leading to a sequence of disturbances in lipid metabolism, such as increased lipid ROS and the blocked transfer of fatty acids from LDs to mitochondria. PGC-1<em>α</em> deficiency worsens the neomycin-induced disorders in lipid metabolism and intensifies the pathological interactions between mitochondria and LDs, as indicated by the exacerbated disturbance of dynamic LD turnover, increased level of oxidized lipids and decreased use of fatty acids. This investigation provides a fresh perspective on the lipid metabolic dysfunction related to mitochondria–LD interactions in drug-induced ototoxicity and nephrotoxicity, potentially providing novel avenues for intervention strategies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4413-4430"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141277434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.08.003
Jiaojiao Yu , Yujin Xiang , Yuzhen Gao , Shan Chang , Ren Kong , Xiaoxi Lv , Jinmei Yu , Yunjie Jin , Chenxi Li , Yiran Ma , Zhenhe Wang , Jichao Zhou , Hongyu Yuan , Shuang Shang , Fang Hua , Xiaowei Zhang , Bing Cui , Pingping Li
Protein kinase C α (PKCα) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms. In this study, we found that PKCα inhibition enhances CD8+ T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKCα as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation through β transducin repeat-containing protein. Notably, the efficacy of PKCα inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo. Clinical analysis revealed that PKCα expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKCα, identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies, and provided a proof of concept for targeting PKCα in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.
{"title":"PKCα inhibitors promote breast cancer immune evasion by maintaining PD-L1 stability","authors":"Jiaojiao Yu , Yujin Xiang , Yuzhen Gao , Shan Chang , Ren Kong , Xiaoxi Lv , Jinmei Yu , Yunjie Jin , Chenxi Li , Yiran Ma , Zhenhe Wang , Jichao Zhou , Hongyu Yuan , Shuang Shang , Fang Hua , Xiaowei Zhang , Bing Cui , Pingping Li","doi":"10.1016/j.apsb.2024.08.003","DOIUrl":"10.1016/j.apsb.2024.08.003","url":null,"abstract":"<div><div>Protein kinase C <em>α</em> (PKC<em>α</em>) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs <em>via</em> unclear molecular mechanisms. In this study, we found that PKC<em>α</em> inhibition enhances CD8<sup>+</sup> T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKC<em>α</em> as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKC<em>α</em>-mediated PD-L1 phosphorylation promotes PD-L1 degradation through <em>β</em> transducin repeat-containing protein. Notably, the efficacy of PKC<em>α</em> inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity <em>in vivo</em>. Clinical analysis revealed that PKC<em>α</em> expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKC<em>α</em>, identified potential therapeutic strategies to avoid tumor evasion <em>via</em> PKC-targeted therapies, and provided a proof of concept for targeting PKC<em>α</em> in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4378-4395"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142186917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.06.019
Peptides are native binders involved in numerous physiological life procedures, such as cellular signaling, and serve as ready-made regulators of biochemical processes. Meanwhile, small molecules compose many drugs owing to their outstanding advantages of physiochemical properties and synthetic convenience. A novel field of research is converting peptides into small molecules, providing a convenient portable solution for drug design or peptidomic research. Endowing properties of peptides onto small molecules can evolutionarily combine the advantages of both moieties and improve the biological druggability of molecules. Herein, we present eight representative recent cases in this conversion and elaborate on the transformation process of each case. We discuss the innovative technological methods and research approaches involved, and analyze the applicability conditions of the approaches and methods in each case, guiding further modifications of peptides to small molecules. Finally, based on the aforementioned cases, we summarize a general procedure for peptide-to-small molecule modifications, listing the technological methods available for each transformation step and providing our insights on the applicable scenarios for these methods. This review aims to present the progress of peptide-to-small molecule modifications and propose our thoughts and perspectives for future research in this field.
{"title":"Transformation of peptides to small molecules in medicinal chemistry: Challenges and opportunities","authors":"","doi":"10.1016/j.apsb.2024.06.019","DOIUrl":"10.1016/j.apsb.2024.06.019","url":null,"abstract":"<div><div>Peptides are native binders involved in numerous physiological life procedures, such as cellular signaling, and serve as ready-made regulators of biochemical processes. Meanwhile, small molecules compose many drugs owing to their outstanding advantages of physiochemical properties and synthetic convenience. A novel field of research is converting peptides into small molecules, providing a convenient portable solution for drug design or peptidomic research. Endowing properties of peptides onto small molecules can evolutionarily combine the advantages of both moieties and improve the biological druggability of molecules. Herein, we present eight representative recent cases in this conversion and elaborate on the transformation process of each case. We discuss the innovative technological methods and research approaches involved, and analyze the applicability conditions of the approaches and methods in each case, guiding further modifications of peptides to small molecules. Finally, based on the aforementioned cases, we summarize a general procedure for peptide-to-small molecule modifications, listing the technological methods available for each transformation step and providing our insights on the applicable scenarios for these methods. This review aims to present the progress of peptide-to-small molecule modifications and propose our thoughts and perspectives for future research in this field.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4243-4265"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141507653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.06.022
Intracellular delivery of biologicals such as peptides, proteins, and nucleic acids presents a great opportunity for innovative therapeutics. However, the endosome entrapment remains a major bottleneck in the intracellular delivery of biomacromolecules, largely limiting their therapeutic potential. Here, we converted a cell-penetrating peptide (CPP), low molecular weight protamine (LMWP), to endosomal escape peptides (EEPs) by masking LMWP with a pH-responsive counter-ionic peptide. The resulting masked CPPs (mLMWP and mLMWP2) effectively promoted the escape of peptide/protein cargoes from endosomes into the cytoplasm. Consequential lysosome repair and lysophagy were initiated upon the endolysosomal leakage. Minimal reactive oxygen species (ROS) elevation or cell death was observed. Based on mLMWP2, we constructed an intracellular protein delivery system containing an antibody as a targeting module, mLMWP2 as an endosomal escape module, and the desired protein cargo. With the HER2-targeting delivery system, we efficiently translocated cyclization recombination enzyme (Cre) and BH3-interacting domain death agonist (BID) into the cytosol of HER2+ cells to exert their biological activity. Thereby, the modular delivery system shows its potential as a promising tool for scientific studies and therapeutic applications.
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