Biochemistry Biochemistry最新文献_第9页

Controlled Enzyme Cargo Loading in Engineered Bacterial Microcompartment Shells. 在工程细菌微室壳中控制酶的装载。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 Epub Date: 2025-03-05 DOI: 10.1021/acs.biochem.4c00709

Nicholas M Tefft, Yali Wang, Alexander Jussupow, Michael Feig, Michaela A TerAvest

{"title":"Controlled Enzyme Cargo Loading in Engineered Bacterial Microcompartment Shells.","authors":"Nicholas M Tefft, Yali Wang, Alexander Jussupow, Michael Feig, Michaela A TerAvest","doi":"10.1021/acs.biochem.4c00709","DOIUrl":"10.1021/acs.biochem.4c00709","url":null,"abstract":"Bacterial microcompartments (BMCs) are nanometer-scale organelles with a protein-based shell that serve to colocalize and encapsulate metabolic enzymes. They may provide a range of benefits to improve pathway catalysis, including substrate channeling and selective permeability. Several groups are working toward using BMC shells as a platform for enhancing engineered metabolic pathways. The microcompartment shell of Haliangium ochraceum (HO) has emerged as a versatile and modular shell system that can be expressed and assembled outside its native host and with non-native cargo. Further, the HO shell has been modified to use the engineered protein conjugation system SpyCatcher-SpyTag for non-native cargo loading. Here, we used a model enzyme, triose phosphate isomerase (Tpi), to study non-native cargo loading into four HO shell variants and begin to understand maximal shell loading levels. We also measured activity of Tpi encapsulated in the HO shell variants and found that activity was determined by the amount of cargo loaded and was not strongly impacted by the predicted permeability of the shell variant to large molecules. All shell variants tested could be used to generate active, Tpi-loaded versions, but the simplest variants assembled most robustly. We propose that the simple variant is the most promising for continued development as a metabolic engineering platform.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1285-1292"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unveiling the Catalytic Mechanism of Abl1 Kinase: A Single-Magnesium Ion Pathway for Phosphoryl Transfer. 揭示Abl1激酶的催化机制：磷酰转移的单镁离子途径。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 Epub Date: 2025-03-05 DOI: 10.1021/acs.biochem.4c00838

Sinisa Bjelic, Stella Hernandez Maganhi, Ran Friedman

{"title":"Unveiling the Catalytic Mechanism of Abl1 Kinase: A Single-Magnesium Ion Pathway for Phosphoryl Transfer.","authors":"Sinisa Bjelic, Stella Hernandez Maganhi, Ran Friedman","doi":"10.1021/acs.biochem.4c00838","DOIUrl":"10.1021/acs.biochem.4c00838","url":null,"abstract":"Abl1, a nonreceptor tyrosine kinase closely related to Src kinase, regulates critical cellular processes like proliferation, differentiation, cytoskeletal dynamics, and response to environmental cues through phosphorylation-driven activation. Dysregulation places it centrally in the oncogenic pathway leading to blood cancers. making it an ideal drug target for small molecule inhibitors. We sought to understand the underlying mechanism of the phosphoryl-transfer step from the ATP molecule to the substrate tyrosine, as carried out by the Abl1 enzyme. By calculating free energy profiles for the reaction using the empirical valence bond representation of the reacting fragments paired with molecular dynamics and free energy perturbation calculations, a combination of several plausible reaction pathways, ATP conformations, and the number of magnesium ion cofactors have been investigated. For the best-catalyzed pathway, which proceeds through a dissociative mechanism with a single magnesium ion situated in Site I, a close agreement was reached with the experimentally determined catalytic rates. We conclude that the catalytic mechanism in Abl1 requires one magnesium ion for efficient catalysis, unlike other kinases, where two ions are utilized. A better overall understanding of the phosphoryl-transfer reactions in Abl1 can be used for type-I inhibitor development and generally contributes to a comprehensive overview of the mechanism for ATP-driven reactions.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1415-1424"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biased Signaling in G Protein-Coupled Receptors: Understanding the Biological Relevance and Tools for Probing Functionally Selective Ligands G蛋白偶联受体的偏置信号：了解生物学相关性和探测功能选择性配体的工具

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 DOI: 10.1021/acs.biochem.4c0087110.1021/acs.biochem.4c00871

Braden S. Fallon, Kathleen E. Rondem, Elizabeth J. Mumby and Justin G. English*,

{"title":"Biased Signaling in G Protein-Coupled Receptors: Understanding the Biological Relevance and Tools for Probing Functionally Selective Ligands","authors":"Braden S. Fallon, Kathleen E. Rondem, Elizabeth J. Mumby and Justin G. English*, ","doi":"10.1021/acs.biochem.4c0087110.1021/acs.biochem.4c00871","DOIUrl":"https://doi.org/10.1021/acs.biochem.4c00871https://doi.org/10.1021/acs.biochem.4c00871","url":null,"abstract":"Biased signaling has transformed pharmacology by revealing that receptors, particularly G protein-coupled receptors (GPCRs), can activate specific intracellular pathways selectively rather than uniformly. This discovery enables the development of targeted therapeutics that minimize side effects by precisely modulating receptor activity. Functionally selective ligands, which preferentially activate distinct signaling branches, have become essential tools for exploring receptor mechanisms and uncovering the complexities of GPCR signaling. These ligands help clarify receptor function in various physiological and pathological contexts, offering profound implications for therapeutic innovation. GPCRs, which mediate a wide range of cellular responses through coupling to G proteins and arrestins, are key pharmacological targets, with nearly a third of FDA-approved drugs acting on them. Recent advancements in biosensor development, multiplex assay platforms, and deep mutational scanning methods are improving our ability to define GPCR signaling, allowing for a better understanding of biased signaling pathways.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":"64 7","pages":"1425–1436 1425–1436"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143737382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Influence of Magnesium Ions and Crowding Agents on Structure and Stability of RNA Aptamers. 镁离子和拥挤剂对RNA适体结构和稳定性的影响。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 Epub Date: 2025-01-10 DOI: 10.1021/acs.biochem.4c00468

Jaskirat Kaur, Rajeev Jain, Sumangal Roychowdhury, Rajanya Roy, Krishnananda Chattopadhyay, Ipsita Roy

{"title":"Influence of Magnesium Ions and Crowding Agents on Structure and Stability of RNA Aptamers.","authors":"Jaskirat Kaur, Rajeev Jain, Sumangal Roychowdhury, Rajanya Roy, Krishnananda Chattopadhyay, Ipsita Roy","doi":"10.1021/acs.biochem.4c00468","DOIUrl":"10.1021/acs.biochem.4c00468","url":null,"abstract":"Aptamers bind to their targets with exceptional affinity and specificity. However, their intracellular application is hampered by the lack of knowledge about the effect of the cellular milieu on the RNA structure/stability. In this study, cellular crowding was mimicked using polyethylene glycol (PEG), and the crucial role of Mg2+ ions in stabilizing the structure of an RNA aptamer was investigated. Increasing the concentration of Mg2+ or PEG increased the thermal stability of the aptamer. The crowding effect lowered the requirement of the Mg2+ ion to form the binding-competent conformer of the aptamer. This suggests that crowding and other factors may compensate for a lower concentration of Mg2+ for proper folding of aptamers inside cells. Selective 2'-hydroxyl acylation and primer extension (SHAPE) probing permitted residue-level analysis of the aptamer. Mg2+ and/or PEG were shown to be involved in increasing the rigidity or flexibility of different regions of the aptamer. Fluorescence correlation spectroscopy showed a significantly low hydrodynamic radius (RH) in the presence of molecular crowders and Mg2+ ions. We believe that the decreased water activity due to crowding may be responsible for reduced RH. Our results show that in a crowded environment, the RNA aptamer was exposed to conformers that were not available to it in simple buffer solutions or solely in the presence of lower concentrations of Mg2+.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1233-1243"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Distinct Mechanism of RNA Recognition by the Transcription Factor GATA1. 转录因子GATA1识别RNA的独特机制

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 Epub Date: 2025-02-25 DOI: 10.1021/acs.biochem.4c00818

Daniella A Ugay, Robert T Batey, Deborah S Wuttke

{"title":"A Distinct Mechanism of RNA Recognition by the Transcription Factor GATA1.","authors":"Daniella A Ugay, Robert T Batey, Deborah S Wuttke","doi":"10.1021/acs.biochem.4c00818","DOIUrl":"10.1021/acs.biochem.4c00818","url":null,"abstract":"Several human transcription factors (TFs) have been reported to directly bind RNA through noncanonical RNA-binding domains; however, most of these TFs remain to be further validated as bona fide RNA-binding proteins (RBPs). Our systematic analysis of RBP discovery data sets reveals a varied set of candidate TF-RBPs that encompass most TF families. These candidate RBPs include members of the GATA family that are essential factors in embryonic development. Investigation of the RNA-binding features of GATA1, a major hematopoietic TF, reveals robust sequence independent binding to RNAs in vitro. Moreover, RNA binding by GATA1 is competitive with DNA binding, which occurs through a shared binding surface spanning the DNA-binding domain and arginine-rich motif (ARM)-like domain. We show that the ARM-like domain contributes substantially to high-affinity DNA binding and electrostatically to plastic RNA recognition, suggesting that the separable RNA-binding domain assigned to the ARM-domain in GATA1 is an oversimplification of a more complex recognition network. These biochemical data demonstrate a unified integration of DNA- and RNA-binding surfaces within GATA1, whereby the ARM-like domain provides an electrostatic surface for RNA binding but does not fully dominate GATA1-RNA interactions, which may also apply to other TF-RBPs. This competitive DNA/RNA binding activity using overlapping nucleic acid binding regions points to the possibility of RNA-mediated regulation of the GATA1 function during hematopoiesis. Our study highlights the multifunctionality of DNA-binding domains in RNA recognition and supports the need for robust characterization of predicted noncanonical RNA-binding domains such as ARM-like domains.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1193-1198"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Major Disease-Related Point Mutation in Spastin Dramatically Alters the Dynamics and Allostery of the Motor. 一个主要的疾病相关的痉挛蛋白点突变显著地改变了运动的动力学和变构。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 Epub Date: 2025-02-26 DOI: 10.1021/acs.biochem.4c00693

Shehani Kahawatte, Amanda C Macke, Carter St Clair, Ruxandra I Dima

{"title":"A Major Disease-Related Point Mutation in Spastin Dramatically Alters the Dynamics and Allostery of the Motor.","authors":"Shehani Kahawatte, Amanda C Macke, Carter St Clair, Ruxandra I Dima","doi":"10.1021/acs.biochem.4c00693","DOIUrl":"10.1021/acs.biochem.4c00693","url":null,"abstract":"Spastin is a microtubule-severing AAA+ ATPase that is highly expressed in neuronal cells and plays a crucial role in axonal growth, branching, and regeneration. This machine oligomerizes into hexamers in the presence of ATP and microtubule carboxy-terminal tails (CTTs). Conformational changes in spastin hexamers, powered by ATP hydrolysis, apply forces to the microtubule, ultimately leading to the severing of the filament. Mutations disrupt the normal function of spastin, impairing its ability to sever microtubules effectively and leading to abnormal microtubule dynamics in neurons characteristic of the set of neurodegenerative disorders called hereditary spastic paraplegias (HSP). Experimental studies have identified the HSP-related R591S (Drosophila melanogaster numbering) mutation as playing a crucial role in spastin. Given its significant role in HSP, we employed a combination of molecular dynamics simulations with machine learning and graph network-based approaches to identify and quantify the perturbations caused by the R591S HSP mutation on spastin's dynamics and allostery with functional implications. We found that the functional hexamer, upon HSP-related mutation, loses the ability to execute the primary motion associated with the severing action. The study of allosteric changes upon the mutation showed that the regions that are most perturbed are those involved in the formation of the interprotomer contacts. The mutation induces rigidity in the allosteric networks of the motor, making it more likely to experience loss of function as applied perturbations would not be easily dissipated by passing through a variety of alternative paths as in the wild-type (WT) spastin.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1293-1307"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fine-Tuning of ATF4 DNA Binding Activity by a Secondary Basic Motif Unique to the ATF-X Subfamily of bZip Transcription Factors. bZip转录因子ATF-X亚家族独有的二级基本基序对ATF4 DNA结合活性的微调。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 Epub Date: 2025-02-24 DOI: 10.1021/acs.biochem.4c00640

Steven Siang, Urval Patel, Manuela Chaves-Mejía, Jeffrey A Purslow, Davit Potoyan, Julien Roche

{"title":"Fine-Tuning of ATF4 DNA Binding Activity by a Secondary Basic Motif Unique to the ATF-X Subfamily of bZip Transcription Factors.","authors":"Steven Siang, Urval Patel, Manuela Chaves-Mejía, Jeffrey A Purslow, Davit Potoyan, Julien Roche","doi":"10.1021/acs.biochem.4c00640","DOIUrl":"10.1021/acs.biochem.4c00640","url":null,"abstract":"The fine-tuning of transcription factor DNA-binding activity is often governed by transient intramolecular interactions between the transactivation domain and the DNA-binding domain. An example of such interaction is found in the transcription factor ATF4, a central regulator of the Integrated Stress Response. In ATF4, dynamic coupling between the transactivation domain and the basic-leucine zipper (bZip) domain modulates the phosphorylation levels of the disordered transactivation domain by casein kinase 2. However, the structural and molecular basis of these interdomain interactions remains poorly understood. This study focuses on a secondary basic motif at the C-terminus of ATF4, which is shared exclusively with its closest paralogue, ATF5. Through a combination of solution NMR spectroscopy, fluorescence polarization assays, and long-timescale molecular simulations, we demonstrate that this secondary basic motif is the primary driver of interdomain coupling between the transactivation and bZip domains of ATF4. Moreover, this motif enhances ATF4's DNA-binding specificity via interaction with the transactivation domain while also potentially facilitating rapid DNA scanning. Our findings reveal the pivotal role of a conserved motif in establishing disorder-mediated interactions that critically modulate ATF4's DNA-binding activity.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1257-1265"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alanine Scanning to Define Membrane Protein-Lipid Interaction Sites Using Native Mass Spectrometry. 丙氨酸扫描定义膜蛋白-脂质相互作用位点使用天然质谱。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 Epub Date: 2025-03-06 DOI: 10.1021/acs.biochem.4c00717

Hiruni S Jayasekera, Farhana Afrin Mohona, Madison J De Jesus, Katherine M Miller, Michael T Marty

{"title":"Alanine Scanning to Define Membrane Protein-Lipid Interaction Sites Using Native Mass Spectrometry.","authors":"Hiruni S Jayasekera, Farhana Afrin Mohona, Madison J De Jesus, Katherine M Miller, Michael T Marty","doi":"10.1021/acs.biochem.4c00717","DOIUrl":"10.1021/acs.biochem.4c00717","url":null,"abstract":"Lipids surrounding membrane proteins interact with different sites on the protein with varying specificities, ranging from highly specific to weak interactions. These interactions can modulate the structure, function, and stability of membrane proteins. Thus, to better understand membrane protein structure and function, it is important to identify the locations of lipid binding and the relative specificities of lipid binding at these sites. In our previous native mass spectrometry (MS) study, we developed a single and double mutant analysis approach to profile the contribution of specific residues toward lipid binding. Here, we extend this method by screening a broad range of mutants of AqpZ to identify specific lipid binding sites and by measuring binding of different lipid types to measure the selectivity of different lipids at selected binding sites. We complemented these native MS studies with molecular dynamics (MD) simulations to visualize lipid interactions at selected sites. We discovered that AqpZ is selective toward cardiolipins (CL) but only at specific sites. Specifically, CL orients with its headgroup facing the cytoplasmic side, and its acyl chains interact with a hydrophobic pocket located at the monomeric interface within the lipid bilayer. Overall, this integrative approach provides unique insights into lipid binding sites and the selectivity of various lipids toward AqpZ, enabling us to map the AqpZ protein structure based on the lipid affinity.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1308-1316"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting Bacterial RNA Polymerase: Harnessing Simulations and Machine Learning to Design Inhibitors for Drug-Resistant Pathogens. 靶向细菌RNA聚合酶：利用模拟和机器学习设计耐药病原体抑制剂。

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 Epub Date: 2025-02-27 DOI: 10.1021/acs.biochem.4c00751

Eshani C Goonetilleke, Xuhui Huang

{"title":"Targeting Bacterial RNA Polymerase: Harnessing Simulations and Machine Learning to Design Inhibitors for Drug-Resistant Pathogens.","authors":"Eshani C Goonetilleke, Xuhui Huang","doi":"10.1021/acs.biochem.4c00751","DOIUrl":"10.1021/acs.biochem.4c00751","url":null,"abstract":"The increase in antimicrobial resistance presents a major challenge in treating bacterial infections, underscoring the need for innovative drug discovery approaches and novel inhibitors. Bacterial RNA polymerase (RNAP) has emerged as a crucial target for antibiotic development due to its essential role in transcription. RNAP is a molecular motor, and its function relies heavily on the dynamic shifts between multiple conformational states. While biochemical and structural experimental methods offer crucial insights into static RNAP-drug interactions, they fall short in capturing the dynamics at a molecular level. By integrating experimental data with advanced computational techniques like Markov State Models (MSMs), Generalized Master Equation (GME) Models and other machine-learning models constructed from molecular dynamics (MD) simulations, researchers can elucidate novel cryptic pockets that open transiently for antibiotic compounds and gain a more nuanced and comprehensive understanding of RNAP-drug interactions. This integrated approach not only deepens our fundamental knowledge but also enables more targeted and efficient antibiotic design strategies. In this Perspective, we highlight how this synergy between experimental and computational methods has the potential to open new pathways for innovative drug design and combination therapies that may help turn the tide in the ongoing battle against antibiotic-resistant bacteria.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1169-1179"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tumor Microenvironment pH-Sensitive Peptidomimetics for Targeted Anticancer Drug Delivery. 用于靶向递送抗癌药物的肿瘤微环境 pH 值敏感拟肽物

IF 2.9 3区生物学

Biochemistry Biochemistry Pub Date : 2025-03-18 Epub Date: 2025-02-27 DOI: 10.1021/acs.biochem.4c00657

Biswanath Maity, Hariharan Moorthy, Thimmaiah Govindaraju

{"title":"Tumor Microenvironment pH-Sensitive Peptidomimetics for Targeted Anticancer Drug Delivery.","authors":"Biswanath Maity, Hariharan Moorthy, Thimmaiah Govindaraju","doi":"10.1021/acs.biochem.4c00657","DOIUrl":"10.1021/acs.biochem.4c00657","url":null,"abstract":"Cell-penetrating peptides (CPPs) are known for their effective intracellular transport of bioactives such as therapeutic proteins, peptides, nucleic acid, and small molecule drugs. However, the excessive cationic charges that promote their membrane permeability result in nonselective delivery and cellular toxicity. In this study, we report a decamer cell-penetrating peptidomimetic, Hkd, designed to selectively deliver anticancer drugs into tumor cells in response to the acidic microenvironment. The pH-sensitive histidine (H) imidazole side chain undergoes protonation in acidic environments, facilitating membrane permeability. The rigid cyclic dipeptide (CDP) core (kd) of Hkd has multiple hydrogen bond donor and acceptor sites, enabling selective interaction-driven cellular uptake. Pharmacokinetic studies revealed the excellent serum stability of Hkd. Cellular uptake studies of Hkd showed improved uptake at a lower pH than physiological pH. Conjugation of Hkd to the anticancer drug camptothecin (Cpt) reduced nonselective drug transport to normal cells while effectively delivering the drug into cancerous cells at the tumor microenvironment pH and retaining the therapeutic potential of the drug. The systematic design of pH-sensitive peptidomimetics offers a viable method to overcome the challenges of stability and selectivity faced by traditional highly cationic CPPs, potentially expanding the application range of this delivery system.","PeriodicalId":28,"journal":{"name":"Biochemistry Biochemistry","volume":" ","pages":"1266-1275"},"PeriodicalIF":2.9,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0