Chemico-Biological Interactions最新文献

{"title":"Ilimaquinone induces apoptosis in gastric cancer cells by inhibiting the signal transducer and activator of the transcription 3 pathway","authors":"Jui-Hsin Su ,&nbsp;Li-Yuan Bai ,&nbsp;Chia-Yung Wu ,&nbsp;Chia-Hsien Feng ,&nbsp;Jing-Ru Weng","doi":"10.1016/j.cbi.2025.111582","DOIUrl":"10.1016/j.cbi.2025.111582","url":null,"abstract":"<div><div>Natural marine products possess pharmacological effects and have been a source of novel drugs for centuries. In this study, we explored the anti-tumor activity and underlying mechanism of action of ilimaquinone, a sesquiterpene quinone from marine sponges, in gastric cancer. Three gastric cancer cell lines (KATO III, SCM-1, and AZ521) were cultured. Cell viability, cell cycle, and apoptosis were determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and flow cytometry. The levels of apoptotic proteins, proteins related to autophagy, and signal transducer and activator of transcription 3 (STAT3) were detected using western blotting. Transient transfection experiments were conducted to assess the expression of STAT3 in the gastric cancer cells. Ilimaquinone inhibited cell growth, caused cell cycle arrest in the S phase, and induced apoptosis. In addition, ilimaquinone modulates autophagy, and the viability of gastric cancer cells decreases upon exposure to a combination of the autophagic inhibitor, chloroquine. Notably, ilimaquinone downregulated the expression of p-STAT3 in a concentration- and time-dependent manner in both gastric cancer cell lines. Moreover, the compound-mediated inhibition of gastric cancer cell proliferation was restored by ectopic STAT3 expression. Collectively, these findings demonstrate the value of ilimaquinone in the treatment of gastric cancer.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111582"},"PeriodicalIF":4.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure of human neuroblastoma SH-SY5Y cells to amphetamine-type stimulants leads to oxidative-antioxidative imbalance associated with DNA damage and acetylcholine antagonism","authors":"Antonio Zandona ,&nbsp;Andreja Jurič ,&nbsp;Blanka Tariba Lovaković ,&nbsp;Alica Pizent ,&nbsp;Dubravka Rašić ,&nbsp;Nevenka Kopjar ,&nbsp;Maja Katalinić ,&nbsp;Arnes Rešić ,&nbsp;Irena Canjuga ,&nbsp;Marijana Neuberg ,&nbsp;Goran Kozina ,&nbsp;Ana Lucić Vrdoljak ,&nbsp;Irena Brčić Karačonji","doi":"10.1016/j.cbi.2025.111579","DOIUrl":"10.1016/j.cbi.2025.111579","url":null,"abstract":"<div><div>Amphetamine-type stimulants (ATSs) are widely abused substances that impair central and peripheral nervous system functions. The mechanisms of their toxicity on human neuronal cells have not been fully clarified yet but include effects on oxidative-antioxidative balance and interaction with synaptic enzymes/receptors. The aims of this study were to determine oxidant/antioxidant status, DNA integrity and the activity of neurotransmitter system components (monoamine oxidase A, MAO-A and nicotinic acetylcholine receptors, nAChR) in human neuroblastoma SH-SY5Y cells after 24-h exposure to different ATSs. In this matter, we first evaluated cell viability by MTS assay. After determination of the concentrations (near IC₂₅) suitable for conduction of the alkaline comet assay, these were further studied for the extent of DNA damage, along with the levels of malondialdehyde, reactive oxygen species (ROS), glutathione (GSH) and activities of antioxidative enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT). The activity of the MAO-A enzyme and nAChR activity were evaluated at concentration range 1–50 μM. Finally, the <em>in silico</em> pharmacokinetic parameters predictions of the tested ATSs were determined. When compared to untreated cells, the most notable result was obtained for amphetamine (AMP), where we observed a significant increase in ROS levels, SOD, GPx and CAT activity, and a decrease in GSH levels. Interestingly, all of the tested ATSs increased the activity of GPx, while the activities of the other enzymes were compound-dependent. The new psychoactive substance (NPS) mephedrone (4-MMC) had a similar effect as AMP, except that it did not affect CAT activity. At the tested concentrations, AMP, methamphetamine (METH) and 4-MMC also showed effects on DNA stability. None of the tested ATSs inhibited MAO-A in the tested concentration range, but AMP, METH, 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) inhibited acetylcholine activation of human nAChR. Taken together, significant induction of oxidative stress parameters, increased level of DNA damage detected and inhibition of nAChR activity indicate potential mechanisms of ATS substances action, and represent the direction for further studies to clarify the toxicological risks associated with ATS and/or NPS consumption.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111579"},"PeriodicalIF":4.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The combined application of cis-cyclo(L-Phe-L-Pro) with antimicrobial proline-based 2,5-diketopiperazines significantly enhances anti-breast cancer activity by selectively targeting cancer stem cells","authors":"Rui Liu ,&nbsp;Bo Sun ,&nbsp;Sa-Ouk Kang ,&nbsp;Yeonju Hong ,&nbsp;Ji-Yoon Yeo ,&nbsp;Jun-Hua Wang ,&nbsp;Min-Kyu Kwak","doi":"10.1016/j.cbi.2025.111565","DOIUrl":"10.1016/j.cbi.2025.111565","url":null,"abstract":"<div><div>Proline-based cyclic dipeptides (CDPs) from lactic acid bacteria are stereochemically diverse molecules, possessing oral bioavailability and significant pharmacological potential. Herein, we developed a robust two-step ion-exchange purification platform to comprehensively isolate 16 structurally defined CDPs from 82-h culture filtrates (CFs) of <em>Lactobacillus plantarum</em> LBP-K10. Utilizing cation (Amberlite IRA-120) and anion (Amberlite IRA-67) exchange chromatography, we generated the K10-CCDP-IV fraction from 82-h acetate membrane-filtered CFs, followed by CH₂Cl₂ extraction to obtain K10-CCDP-IV-MC. Additional test agents included LBP-K10-CF (CH₂Cl₂-unextracted CF), LBP-K10-MC (CH₂Cl₂-extracted CF), and a single <em>ci</em>s-cyclo(L-Phe-L-Pro). LC-MS-linked HPLC-based time-course quantification revealed peaks in total CDP concentration at 82 h, with notable increases in fractions F6, F7, F12, F16, and F17. <em>In vitro</em> studies using MDA-MB-231 breast cancer cells demonstrated that both K10-CCDP-IV-MC and LBP-K10-MC significantly suppressed cell proliferation by inducing G1-phase arrest and mitochondria-mediated apoptosis, as evidenced by the increased expression of cytochrome <em>c</em>, cleaved caspase-3, and BAD, along with the downregulation of Bcl-2. Furthermore, both treatments inhibited cancer stem cell characteristics, including a reduction in the CD133⁺ subpopulation, repression of Oct4, and inhibition of sphere formation. <em>In vivo</em>, oral administration of LBP-K10-MC in xenograft-bearing SCID mice resulted in a significant reduction in tumor volume without systemic toxicity or adverse effects. These findings underscore the therapeutic relevance and preclinical validation of CDP-based consortia as orally deliverable, bioavailable, and multifunctional anticancer agents derived from a single probiotics. This supports their translational potential in dietary and therapeutic applications, offering a scalable, food-grade platform for the production of functional CDPs targeting breast cancer stemness.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111565"},"PeriodicalIF":4.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144125073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholinesterase activity modulators: Evaluation of dodecylaminoquinuclidines as inhibitors of human AChE and BChE","authors":"Ana-Marija Lulić ,&nbsp;Lucija Marcelić ,&nbsp;Alma Ramić ,&nbsp;Andreja Radman Kastelic ,&nbsp;Antonio Zandona ,&nbsp;Nikola Maraković ,&nbsp;Ines Primožič ,&nbsp;Maja Katalinić","doi":"10.1016/j.cbi.2025.111567","DOIUrl":"10.1016/j.cbi.2025.111567","url":null,"abstract":"<div><div>In this study, we investigated the inhibitory activity of novel dodecylaminoquinuclidines (QAs) on neurotransmitter-hydrolyzing enzymes, specifically acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Following our previous findings, we modified the structure of a lead compound to develop more potent modulators of cholinesterase activity. The search for such inhibitors remains a key focus in the therapeutic management of organophosphate poisoning and various neurological disorders. For the design, we retained the aliphatic side linker and introduced various benzyl-based substituents to the quinuclidinium core, resulting in a set of 11 new compounds. All of these derivatives exhibited reversible inhibition of cholinesterase within the micromolar concentration range. The most significant factor affecting inhibition was the positional change of a specific group on the benzene ring, shifting from the <em>meta</em> to the <em>para</em> position. Specifically, analogues with groups in the <em>meta</em> position showed a stronger inhibition of AChE, whereas the <em>para</em> position was more effective for BChE. The most potent inhibitor featured a –CH₃ or -Br substituent, with a <em>K</em>_i of around 1.7–2.0 μM (<em>meta</em>-position) for AChE and 0.3–0.5 μM (<em>para</em>-position) for BChE. Additionally, we assessed the cytotoxicity of these compounds on human neuronal SH-SY5Y cells, as their intended target in the body. As all tested quinuclidine derivatives demonstrated a certain level of cytotoxicity within the range of 1.5–17 μM, further research is needed to explore this effect, and to validate or negate their potential for development into therapeutic agents.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111567"},"PeriodicalIF":4.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paris saponin VII restrains PD-L1 mediated immune evasion through the AKT1 and STAT3 signaling pathways","authors":"Yudi Wang ,&nbsp;Yanli Li ,&nbsp;Yurui Zhang ,&nbsp;Yitong Li ,&nbsp;Leilei Zhao ,&nbsp;Lanxin Tong ,&nbsp;Xiao Zhu ,&nbsp;Jianyong Wang ,&nbsp;Yucui Dong","doi":"10.1016/j.cbi.2025.111562","DOIUrl":"10.1016/j.cbi.2025.111562","url":null,"abstract":"<div><div>Glioblastoma (GBM) represents a highly aggressive and fatal type of brain cancer. Paris saponin VII (PS VII) is noteworthy for its potential anti-tumor properties, yet the anti-tumor effect and underlying mechanism of PS VII on GBM remain unclear. This study demonstrated that PS VII inhibited the proliferation and migration rates of GBM cells. PS VII induced cell cycle arrest at the G2/M phase, which was linked to significant reductions in the expression of CDK1, Cyclin D1 and CDK2. Furthermore, PS VII triggered cells apoptosis in a dose-dependent manner by up-regulating the expression of Bax while down-regulating that of Bcl-2, leading to the activation of Caspase-3 and PARP. Further investigation revealed that PS VII effectively suppressed the expression of PD-L1, a key factor in the development of tumors. Additionally, PS VII decreased PD-L1 expression by modulating the activities of AKT1 and STAT3 signaling pathways. In tumor/T cells co-culture system, PS VII restored the activation of T cells by inhibiting PD-L1 expression. Notably, PS VII inhibited GBM cells proliferation, migration by reducing PD-L1. <em>In vivo</em> study showed that PS VII reduced the volume and size of tumors, and achieved better therapeutic effects at higher concentrations. These results revealed PS VII's previously unrecognized anti-tumor effects on GBM, suggesting its potential as a therapeutic drug for GBM treatment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111562"},"PeriodicalIF":4.7,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetyl alkannin, a Shikonin monomer, inhibits the ATM/DDR pathway by targeting ATM and sensitizes cisplatin in solid tumors","authors":"Xinwen Xu ,&nbsp;Jianyi Gu ,&nbsp;Peiwen Yang ,&nbsp;Lifang Huang ,&nbsp;Na Zhao ,&nbsp;Jingjing Tang ,&nbsp;Zifeng Liang ,&nbsp;Qiang Li ,&nbsp;Shunqian Wen ,&nbsp;Jianwei Jiang ,&nbsp;Qing Zhang","doi":"10.1016/j.cbi.2025.111559","DOIUrl":"10.1016/j.cbi.2025.111559","url":null,"abstract":"<div><div>Platinum-based chemotherapy is limited by drug resistance and severe adverse effects. Although the DNA damage response (DDR) is known to affect drug sensitivity across cancer types, the role of its upstream regulator ATM in modulating cisplatin (DDP) resistance remains unclear. In this study, we investigated the role of the ATM/DDR pathway to DDP resistance and proposed a potential targeted strategy. Bioinformatics analysis revealed significant overexpression of ATM and RAD51 in liver and lung cancers, which correlated with poor survival (<em>p</em> &lt; 0.05). <em>In vitro</em> assays showed that DDP activated ATM to initiate the downstream DDR, thereby promoting chemoresistance; inhibition of ATM using KU-55933 or siRNA enhanced the anticancer effect of DDP. Among screened Shikonin derivatives, acetyl alkannin emerged as the most potent ATM-targeting analogue. Combination treatment with low-dose acetyl alkannin (2.5 μM or 2.6 μM) and DDP increased DDP sensitivity 8.0-fold in Huh-7 liver cancer cells and 22.5-fold in A549 lung cancer cells. Mechanistically, acetyl alkannin targets ATM and induces its caspase-dependent degradation, suppressing DDR signaling and promoting apoptosis. <em>In vivo</em> xenograft experiments confirmed the superior tumor growth inhibition of the combination treatment. These findings establish ATM-mediated DDR activation as a central mechanism of DDP resistance and identify acetyl alkannin as a candidate sensitizer for platinum-based chemotherapy.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111559"},"PeriodicalIF":4.7,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin's paradox: From therapeutic benefits to toxicity warnings","authors":"Mohammad Amrollahi-Sharifabadi ,&nbsp;Toheeb Olalekan Oladejo ,&nbsp;Adedayo Sheu Ibrahim ,&nbsp;Bushra Shakoor ,&nbsp;Omid Mehrpour ,&nbsp;Goudarz Sadeghi-Hashjin ,&nbsp;Sara Gonçalves","doi":"10.1016/j.cbi.2025.111556","DOIUrl":"10.1016/j.cbi.2025.111556","url":null,"abstract":"<div><div>Melatonin is an endogenous chemical predominantly synthesized in the pineal gland, widely recognized for its hormonal roles, such as regulating sleep and circadian rhythms. Through mechanisms such as anti-oxidative reduction, anti-inflammatory, and immunomodulation, it is suggested that melatonin exhibits biochemical properties in <em>in vitro</em> conditions. Beyond these functions, melatonin has garnered attention for its pharmacological benefits, particularly as a therapeutic agent that is exogenously administered as a supplement in various diseases ranging from insomnia to immunological and gastrointestinal disorders. However, emerging studies highlight potential toxicological concerns associated with exogenous melatonin use, especially in specific populations. This review provided a comprehensive exploration of melatonin's dual role as a therapeutic and potentially toxic agent. It summarized what is currently known about its pharmacological, toxicological, and biochemical characteristics as well as toxicity mechanisms, and safety concerns in susceptible groups. By highlighting new knowledge gaps about melatonin's clinical uses, the study opens the door for further studies to maximize its therapeutic benefits while maintaining its safety.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111556"},"PeriodicalIF":4.7,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stereoisomeric mitomycins interstrand crosslinks differently impact gene expression in MCF-7 and K562 cancer cells","authors":"Lissette Delgado-Cruzata ,&nbsp;Owen Zacarias ,&nbsp;Shu-Yuan Cheng ,&nbsp;Jaxon Tartaglia ,&nbsp;Melissa Rosas ,&nbsp;Christina Gonzalez ,&nbsp;Elise Champeil","doi":"10.1016/j.cbi.2025.111564","DOIUrl":"10.1016/j.cbi.2025.111564","url":null,"abstract":"<div><div>Mitomycin C (MC) is an anticancer drug used to treat stomach, anal and lung cancers. The main cytotoxicity of MC is due to its ability to form interstrand crosslinks with DNA (ICLs). The stereochemical configuration at C1″ of MC major ICL is <em>R</em> (α-ICL). In contrast, decarbamoylmitomycin C, a synthetic derivative of MC, generates the major <em>S</em> stereoisomeric ICL (β-ICL). Here, we investigated the effect of the stereochemical configuration of the α/β-ICL on the cellular response by focusing on gene expression changes in MCF-7 and K562 cell lines, one with wild type and the other with mutated TP53, upon treatment with both ICLs. We transfected both cell lines with duplex oligonucleotides containing either the α- or β-ICL at a single site and extracted RNA for transcriptome analysis. Results show that the stereochemical configuration of the α/β-ICL is responsible for distinct gene expression changes in MCF-7 and K562 cells. Our data also show that, in MCF-7 cells, α-ICL treatment triggers a strong increase in <em>CDKN1A</em> expression which is also observed at the protein level, contrary to what happens upon β-ICL treatment. In addition, β-ICL treatment led to a strong downregulation of a greater number of genes than the α-ICL in both cell lines, in particular in K562 cells, which harbor a TP53 mutation. This suggests that the β-ICL toxicity relies on a mechanism which leads to an overall downregulation of gene expression and may explain the greater toxicity of DMC toward TP53 mutant cells.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111564"},"PeriodicalIF":4.7,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The roles of YY1 in reproductive system: an overview","authors":"Yinan Wang ,&nbsp;Songming He ,&nbsp;Qin Huang ,&nbsp;Jing Yang ,&nbsp;Chaogang Yang ,&nbsp;Jinli Ding","doi":"10.1016/j.cbi.2025.111560","DOIUrl":"10.1016/j.cbi.2025.111560","url":null,"abstract":"<div><div>Yin Yang 1 (YY1) is a highly conserved multifunctional transcription factor with multiple biological functions including cell proliferation, differentiation and transcriptional regulation. In recent years, the discovery of the functional activity of YY1 in the reproductive tissues of animals, including humans has attracted more and more attention. YY1 plays important roles in the development of follicular, embryo and placenta, as well as spermatogenesis. In addition, the role of YY1 in reproductive diseases including infertility, polycystic ovarian syndrome, recurrent spontaneous abortion (RSA), and gynecological tumor has been demonstrated. In the present review, we aimed to systematically introduce the expression and functions of YY1 in the reproductive system, providing new recommendations for future research areas.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"417 ","pages":"Article 111560"},"PeriodicalIF":4.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144095959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent progress of proline endopeptidase ligands and their effects on protein-protein interactions","authors":"Kun-Jie Bian ,&nbsp;Xiaoze Bao ,&nbsp;Xiao-Dong Li ,&nbsp;Damien Bonne ,&nbsp;Li-Wei Zou","doi":"10.1016/j.cbi.2025.111557","DOIUrl":"10.1016/j.cbi.2025.111557","url":null,"abstract":"<div><div>Proline endopeptidase (PREP), as a serine protease, plays a crucial role in human physiology and pathology, and is intricately linked to the genesis and progression of a spectrum of illnesses. The fluorescent substrates currently used for PREP lack ideal specificity and are unable to specifically detect PREP activity under physiological conditions. This limitation, to some extent, hinders the in-depth investigation of its physiological and pathophysiological functions. Beyond its enzymatic capabilities, PREP's physiological functions extend to the modulation of protein-protein interactions (PPIs), a dimension whose significance is only beginning to be recognized, and investigations into how PREP inhibitors might influence these PPIs remain sparse. Therefore, based on the outline of the distribution and structural characteristics of PREP, this review systematically summarized the structure-activity relationship (SAR) of PREP ligands concerning their potency and specificity, the associated recognition mechanisms, as well as the regulatory impact of PREP ligands on PPIs. Finally, the obstacles and future prospects of PREP ligands were emphasized, in order to provide suggestions and help for the design and development of PREP specific substrates and inhibitors.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"416 ","pages":"Article 111557"},"PeriodicalIF":4.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}