Bioconjugate Chemistry Bioconjugate最新文献

{"title":"Gastrodin Liposomes Block Crosstalk between Astrocytes and Glioma Cells via Downregulating Cx43 to Improve Antiglioblastoma Efficacy of Temozolomide.","authors":"Yangjie Song, Qi Huang, Qing Pu, Shuting Ni, Wenhao Zhu, Wen Zhao, Hongzhi Xu, Kaili Hu","doi":"10.1021/acs.bioconjchem.4c00300","DOIUrl":"10.1021/acs.bioconjchem.4c00300","url":null,"abstract":"<p><p>The crosstalk between glioma cells and astrocytes plays a crucial role in developing temozolomide (TMZ) resistance of glioblastomas, together with the existence of the BBB contributing to the unsatisfactory clinical treatment of glioblastomas. Herein, we developed a borneol-modified and gastrodin-loaded liposome (Bo-Gas-LP), with the intent of enhancing the efficacy of TMZ therapy after intranasal administration. The results showed that Bo-Gas-LP improved GL261 cells' sensitivity to TMZ and prolonged survival of GL261-bearing mice by blocking the crosstalk between astrocytes and glioblastoma cells with the decrease of Cx43. Our study showed that intranasal Bo-Gas-LP targeting the crosstalk in glioblastoma microenvironments proposed a promising targeted therapy idea to overcome the current therapeutic limitations of TMZ-resistant glioblastomas.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1380-1390"},"PeriodicalIF":4.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing Cell Aggregation and Migration via Double-Click Cross-Linking with Azide-Modified Hyaluronic Acid.","authors":"Fumiya Sato, Hernandez Paniagua Liliana Alejandra, Hitoshi Takemae, Natsuko F Inagaki, Taichi Ito, Masayuki Tera","doi":"10.1021/acs.bioconjchem.4c00221","DOIUrl":"10.1021/acs.bioconjchem.4c00221","url":null,"abstract":"<p><p>We present a novel approach to the formation of cell aggregates by employing click chemistry with water-soluble zwitterionic dibenzo cyclooctadiyne (WS-CODY) and azide-modified hyaluronic acid (HA-N₃) as a linker to facilitate rapid and stable cell aggregation. By optimizing the concentrations of HA-N₃ and WS-CODY, we achieved efficient cross-linking between azide-modified cell surfaces and HA-N₃, generating cell aggregates within 10 min, and the resulting aggregates remained stable for up to 5 days, with cell viability maintained at approximately 80%. Systematic experiments revealed that a stoichiometric balance between HA-N₃ and WS-CODY is important for effective cross-linking, highlighting the roles of both cell-surface azide modification and HA in the aggregate formation. We also investigated the genetic basis of altered cell behavior within these aggregates. Transcriptome analysis (RNA-seq) of aggregates postcultivation revealed a marked fluctuation of genes associated with 'cell migration' and 'cell adhesion', including notable changes in the expression of <i>HYAL1</i>, <i>ICAM-1</i>, <i>CEACAM5</i> and <i>RHOB</i>. These findings suggest that HA-N₃-mediated cell aggregation can induce intrinsic cellular responses that not only facilitate cell aggregate formation but also modulate cell-matrix interactions. We term this phenomenon 'chemo-resilience', The simplicity and efficacy of this click chemistry-based approach suggest it may have broad applicability for forming cell aggregates and modulating cell-matrix interactions in tissue engineering and regenerative medicine.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1318-1323"},"PeriodicalIF":4.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclohexanediamine Triazole (CHDT) Functionalization Enables Labeling of Target Molecules with Al¹⁸F/⁶⁸Ga/¹¹¹In.","authors":"Wiebke Sihver, Martin Walther, Martin Ullrich, Anne-Kathrin Nitt-Weber, Jenny Böhme, Falco Reissig, Magdalena Saager, Kristof Zarschler, Christin Neuber, Jörg Steinbach, Klaus Kopka, Hans-Jürgen Pietzsch, Robert Wodtke, Jens Pietzsch","doi":"10.1021/acs.bioconjchem.4c00313","DOIUrl":"10.1021/acs.bioconjchem.4c00313","url":null,"abstract":"<p><p>The Al¹⁸F-labeling approach offers a one-step access to radiofluorinated biomolecules by mimicking the labeling process for radiometals. Although these labeling conditions are considered to be mild compared to classic radiofluorinations, improvements of the chelating units have led to the discovery of <b>(±)-H</b>_<b>3</b><b>RESCA</b>, which allows Al¹⁸F-labeling already at ambient temperature. While the suitability of <b>(±)-H</b>_<b>3</b><b>RESCA</b> for functionalization and radiofluorination of proteins is well established, its use for small molecules or peptides is less explored. Herein, we advanced this acyclic pentadentate ligand by introducing an alkyne moiety for the late-stage functionalization of biomolecules via click chemistry. We show that in addition to Al¹⁸F-labeling, the cyclohexanediamine triazole (CHDT) moiety allows stable complexation of ⁶⁸Ga and ¹¹¹In. Three novel CHDT-functionalized PSMA inhibitors were synthesized and their Al¹⁸F-, ⁶⁸Ga-, and ¹¹¹In-labeled analogs were subjected to a detailed <i>in vitro</i> radiopharmacological characterization. Stability studies <i>in vitro</i> in human serum revealed among others a high kinetic inertness of all radiometal complexes. Furthermore, the Al¹⁸F-labeled PSMA ligands were characterized for their biodistribution in a LNCaP derived tumor xenograft mouse model by PET imaging. One radioligand, <b>Al[</b>^<b>18</b><b>F]F-CHDT-PSMA-1</b>, bearing a small azidoacetyl linker at the glutamate-urea-lysine motif, provided an <i>in vivo</i> performance comparable to that of <b>[</b>^<b>18</b><b>F]PSMA-1007</b> but with even higher tumor-to-blood and tumor-to-muscle ratios at 120 min <i>p.i.</i> Overall, our results highlight the suitability of the novel CHDT moiety for functionalization and radiolabeling of small molecules or peptides with Al¹⁸F, ⁶⁸Ga, and ¹¹¹In and the triazole ring seems to entail favorable pharmacokinetic properties for molecular imaging purposes.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1402-1416"},"PeriodicalIF":4.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid Nanoparticles for Brain Tumor Theranostics: Challenges and Status.","authors":"Navneet Kaur, Priyadarshi Gautam, Dibyani Nanda, Avtar Singh Meena, Asifkhan Shanavas, Rajendra Prasad","doi":"10.1021/acs.bioconjchem.4c00293","DOIUrl":"10.1021/acs.bioconjchem.4c00293","url":null,"abstract":"<p><p>Lipid nanoparticles have been recognized as a powerful weapon for delivering various imaging and therapeutic agents to the localized solid tumors, especially brain tumors individually or in combination. Promisingly, lipid-based nanosystems have been considered as safe delivery systems which are even approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). One recent spotlight of lipid nanoparticles as COVID-19 mRNA vaccines where lipid nanoparticles play an important role in effectively protecting and delivering mRNA to the desired cells. As of now, successive progress in lipid-based nanocarriers, viz., nanoliposomes, solid lipid nanoparticles, ionizable lipid nanostructures, etc., with better biochemical and biophysical stabilities, has been noticed and reported. Moreover, lipid nanostructures have been considered as versatile therapeutics platforms for a variety of diseases due to their biocompatibility, ability to protect and deliver therapeutics to the localized site, and better reproducibility and reliability. However, lipid nanoparticles still face morphological and biochemical changes upon their <i>in vivo</i> administration. These changes alter the specific biological and pathological response of lipid nanoparticles during their personalized brain tumor theranostics. Second, lipid nanomedicine still faces major challenges of zero premature leakage of loaded cargo, long-term colloidal stability, and off targeting. Herein, various lipid-based nanomedicines for brain tumor imaging and therapeutics \"theranostics\" have been reviewed and summarized considering major aspects of preclinical and clinical studies. On the other hand, engineering and biological challenges of lipid theranostics systems with relevant advantages and guidelines for clinical practice for different brain tumors have also been discussed. This review provides in-depth knowledge of lipid nanoparticle-based theranostics agents for brain tumor imaging and therapeutics.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1283-1299"},"PeriodicalIF":4.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Situ Polymerization for Manufacture of Multifunctional Delivery Systems for Transcellular Delivery of Nucleic Acids.","authors":"Jun Liu, Yanhua Li, Kehui Zhou, Shijia Zhang, Yue Wang, Xiumei Wang, Xiabin Lan, Qixian Chen, Yan Zhao","doi":"10.1021/acs.bioconjchem.4c00319","DOIUrl":"10.1021/acs.bioconjchem.4c00319","url":null,"abstract":"<p><p>Electrostatic self-assembly between negatively charged nucleic acids and cationic materials is the basis for the formulation of the delivery systems. Nevertheless, structural disintegration occurs because their colloidal stabilities are frequently insufficient in a hostile biological environment. To overcome the sequential biological barriers encountered during transcellular gene delivery, we attempted to use in situ polymerization onto plasmid DNA (pDNA) with a variety of functional monomers, including <i>N</i>-(3-aminopropyl)methacrylate, (aminopropyl)methacrylamide hydrochloride, 1-vinylimidazole, and 2-methacryloyloxyethylphosphorylcholine and <i>N</i>,<i>N</i>'-bis(acryloyl) cystamine. The covalently linked monomers could polymerize into a network structure on top of pDNA, providing excellent structural stability. Additionally, the significant proton buffering capacity of 1-vinylimidazole is expected to aid in the release of pDNA payloads from acidic and digestive endolysosomes. In addition, the redox-mediated cleavage of the disulfide bond in <i>N</i>,<i>N</i>'-bis(acryloyl)cystamine allows for the selective cleavage of the covalently linked network in the cytosolic microenvironment. This is due to the high intracellular level of glutathione, which promotes the liberation of pDNA payloads in the cell interiors. The proposed polymerization strategies resulted in well-defined nanoscale pDNA delivery systems. Excellent colloidal stabilities were observed, even when incubated in the presence of high concentrations of heparin (10 mg/mL). In contrast, the release of pDNA was confirmed upon incubation in the presence of glutathione, mimicking the intracellular microenvironment. Cell transfection experiments verified their efficient cellular uptake and gene expression activities in the hard-transfected MCF-7 cells. Hence, the polymerization strategy used in the fabrication of covalently linked nonviral gene delivery systems shows promise in creating high-performance gene delivery systems with diverse functions. This could open new avenues in cellular microenvironment engineering.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1417-1428"},"PeriodicalIF":4.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Data-Driven Design of Novel Polymer Excipients for Pharmaceutical Amorphous Solid Dispersions.","authors":"Elena J Di Mare, Ashish Punia, Matthew S Lamm, Timothy A Rhodes, Adam J Gormley","doi":"10.1021/acs.bioconjchem.4c00294","DOIUrl":"10.1021/acs.bioconjchem.4c00294","url":null,"abstract":"<p><p>About 90% of active pharmaceutical ingredients (APIs) in the oral drug delivery system pipeline have poor aqueous solubility and low bioavailability. To address this problem, amorphous solid dispersions (ASDs) embed hydrophobic APIs within polymer excipients to prevent drug crystallization, improve solubility, and increase bioavailability. There are a limited number of commercial polymer excipients, and the structure-function relationships which lead to successful ASD formulations are not well-documented. There are, however, certain solid-state ASD characteristics that inform ASD performance. One characteristic shared by successful ASDs is a high glass transition temperature (<i>T</i>_g), which correlates with higher shelf stability and decreased drug crystallization. We aim to identify how polymer features such as side chain geometry, backbone methylation, and hydrophilic-lipophilic balance impact <i>T</i>_g to design copolymers capable of forming high-<i>T</i>_g ASDs. We tested a library of 50 ASD formulations (18 previously studied and 32 newly synthesized) of the model drug probucol with copolymers synthesized through automated photoinduced electron/energy transfer-reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization. A machine learning (ML) algorithm was trained on the <i>T</i>_g data to identify the major factors influencing <i>T</i>_g, including backbone methylation and nonlinear side chain geometry. In both polymer alone and probucol-loaded ASDs, a Random Forest Regressor captured structure-function trends in the data set and accurately predicted <i>T</i>_g with an average <i>R</i>² > 0.83 across a 10-fold cross validation. This ML model will be used to predict novel copolymers to design ASDs with high <i>T</i>_g, a crucial factor in predicting ASD success.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1363-1372"},"PeriodicalIF":4.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sortase-Mediated Site-Specific Conjugation to Prepare Fluorine-18-Labeled Nanobodies.","authors":"Falguni Basuli, Jianfeng Shi, Eric Lindberg, Stanley Fayn, Woonghee Lee, Mitchell Ho, Dima A Hammoud, Ross W Cheloha, Rolf E Swenson, Freddy E Escorcia","doi":"10.1021/acs.bioconjchem.4c00264","DOIUrl":"10.1021/acs.bioconjchem.4c00264","url":null,"abstract":"<p><p>Single-domain antibodies, or nanobodies (Nbs), are promising biomolecules for use in molecular imaging due to their excellent affinity, specificity, and fast clearance from the blood. Given their short blood half-life, pairing Nbs with short-lived imaging radioisotopes is desirable. Because fluorine-18 (¹⁸F) is routinely used for clinical imaging, it is an attractive radioisotope for Nbs. We report a novel sortase-based, site-specific ¹⁸F-labeling method applied to three nanobodies. Labeled nanobodies were synthesized either by a two-step indirect radiolabeling method in one pot or by a one-step direct labeling method using a sortase-mediated conjugation of either the radiolabeled chelator (H-GGGK((±)-Al[¹⁸F]FH₃RESCA)-NH₂) or the unlabeled chelator (H-GGGK((±)-H₃RESCA)-NH₂) followed by labeling with Al[¹⁸F]F, respectively. The overall radiochemical yields were 15-43% (<i>n</i> = 22, decay-corrected) in 70 min (indirect labeling) and 23-58% (<i>n</i> = 12, decay-corrected) in 50 min (direct labeling). The radiochemical purities of the labeled nanobodies prepared by both methods were >98% with a specific activity of 400-600 Ci/mmol (<i>n</i> = 22) for each of the three Nbs tested and exhibited excellent stability profiles under physiological conditions. This simple, site-specific, reproducible, and generalizable ¹⁸F-labeling method to prepare nanobodies (Nb-Al[¹⁸F]F-RESCA) or other low molecular weight biomolecules can easily be adopted in various settings for preclinical and clinical studies.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1335-1342"},"PeriodicalIF":4.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanosized Porphyrin-Containing Covalent Organic Polymer to Enhance Ferroptosis in Photodynamic Treatment of Tumor Cells via Glutathione Depletion.","authors":"Jiahao Zhang, Anna Zhang, Siyu Liu, Zhipeng Dong, Junkai Zhao, Yufeng Sun, Qiuxian Wei, Dan Wang, Saifei Wang, Anping Yu, Zhong Rui Li, Ran Yan, Yue Wang","doi":"10.1021/acs.bioconjchem.4c00355","DOIUrl":"10.1021/acs.bioconjchem.4c00355","url":null,"abstract":"<p><p>A porphyrin-containing nanoscale covalent organic polymer (COP) was fabricated from 5,10,15,20-tetra(4-carboxyphenyl)porphyrin (TCPP) and cystamine via an acylation reaction. On the one hand, TCPP can induce tumor cell death by laser irradiation. Due to the presence of disulfide bonds of cystamine which can react with glutathione, it exhibits depletion of glutathione and accumulation of peroxides in tumor cells. Ultimately by the hyaluronic acid to encapsulate the COP to get S-COP@HA, the nanoparticle with a size of 168.6 nm also exhibits good tumor accumulation and biosafety. Significant inhibition of tumor cell growth was observed after two consecutive doses of S-COP@HA at relatively low laser densities. This combination therapy was proved to reduce the level of reduced glutathione in tumor cells, where ferroptosis occurs after photodynamic treatment. Overall, this study presents a potent, good therapeutic option for the effective enhancement of photodynamic therapy by glutathione depletion.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1450-1458"},"PeriodicalIF":4.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of an FAP-Targeted PET Probe Based on a Novel Quinolinium Molecular Scaffold.","authors":"Lei Li, Rui Cao, Kaixin Chen, Chunrong Qu, Kun Qian, Jia Lin, Renda Li, Chaoquan Lai, Xiao Wang, Zijian Han, Zhijian Xu, Liping Zhou, Shaoli Song, Weiliang Zhu, Zhen Cheng","doi":"10.1021/acs.bioconjchem.4c00214","DOIUrl":"10.1021/acs.bioconjchem.4c00214","url":null,"abstract":"<p><p>Fibroblast activation protein (FAP) has recently gained significant attention as a promising tumor biomarker for both diagnosis and therapeutic applications. A series of radiopharmaceuticals based on fibroblast activation protein inhibitors (FAPIs) have been developed and translated into the clinic. Though some of them such as radiolabeled FAPI-04 probes have achieved favorable in vivo imaging performance, further improvement is still highly desired for obtaining radiopharmaceuticals with a high theranostics potential. In this study, we innovatively designed an FAPI ligand SMIC-3002 by changing the core quinoline motif of FAPI-04 to the quinolinium scaffold. The engineered molecule was further radiolabeled with ⁶⁸Ga to generate a positron emission tomography (PET) probe, [⁶⁸Ga]Ga-SMIC-3002, which was then evaluated in vitro and in vivo. [⁶⁸Ga]Ga-SMIC-3002 demonstrated high in vitro stability, nanomolar affinity for FAP (8 nM for protein, 23 nM for U87MG cells), and specific uptake in FAP-expressing tumors, with a tumor/muscle ratio of 19.1 and a tumor uptake of 1.48 ± 0.03 ID/g% at 0.5 h in U87MG tumor-bearing mice. In summary, the quinolinium scaffold can be successfully used for the development of the FAP-targeted tracer. [⁶⁸Ga]Ga-SMIC-3002 not only shows high potential for clinical translation but also offers insights into designing a new generation of FAPI tracers.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1309-1317"},"PeriodicalIF":4.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regiospecific Coelenterazine Analogs for Bioassays and Molecular Imaging.","authors":"Genta Kamiya, Nobuo Kitada, Tadaomi Furuta, Suresh Thangudu, Arutselvan Natarajan, Ramasamy Paulmurugan, Sung-Bae Kim, Shojiro A Maki","doi":"10.1021/acs.bioconjchem.4c00303","DOIUrl":"10.1021/acs.bioconjchem.4c00303","url":null,"abstract":"<p><p>Bioluminescence (BL) generated by luciferase-coelenterazine (CTZ) reactions is broadly employed as an optical readout in bioassays and in vivo molecular imaging. In this study, we demonstrate a systematic approach to elucidate the luciferase-CTZ binding chemistry with a full set of regioisomeric CTZ analogs, where all the functional groups were regiochemically modified. When the chemical structures were categorized into Groups 1-6, the even-numbered Groups (2, 4, and 6) of the CTZ analogs are found to be exceptionally bright with NanoLuc enzyme. A CTZ analogue <b>M2</b> was the brightest with NanoLuc and the reason was deciphered by a computational analysis of the binding modes. We also report that (i) the regioisomeric CTZ analogs collectively create unique intensity patterns according to each marine luciferase, (ii) the quantitative structure-activity relationship analysis revealed the roles of respective functional groups of CTZ analogs, and (iii) the regioisomeric CTZ analogs also exert red shifts of the BL spectra and color variation: that is, the λ_max values are near 500 nm with NanoLuc, near 530 nm with ALuc16, and near 570 nm with RLuc86SG. The advantages of the regioisomeric CTZ analogs were finally demonstrated using (i) a dual-luciferase system with <b>M2</b>-specific NanoLuc and native CTZ-specific ALuc16, (ii) an estrogen activatable single-chain BL probe by imaging, and (iii) BL imaging of live mice bearing tumors expressing NanoLuc and RLuc8.6SG. This study is the first systematic approach to elucidate the regiochemistry in BL imaging studies. This study provides new insights into how CTZ analogs regiochemically work in BL reporter systems and guides the specific applications to molecular imaging.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":"1391-1401"},"PeriodicalIF":4.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}