{"title":"New Tetraphenylethylene Benzoic Acid Derivatives as Antibacterial Agents for Gram-Positive Bacteria with Ultralow Inhibition Concentration","authors":"Xuefan Guo, , , Yanghan Peng, , , Mingge Zhang, , , Kunyi Wang, , , Guoyang Zhang, , , Jiguang Li, , , Zixuan Zhang, , , Rongbo Li*, , and , Zhuo Wang*, ","doi":"10.1021/acs.bioconjchem.5c00448","DOIUrl":"10.1021/acs.bioconjchem.5c00448","url":null,"abstract":"<p >The misuse of antibiotics has intensified the emergence of drug-resistant bacteria. The diversity of chemical structures offers a crucial foundation for developing novel small-molecule antibacterials. New chemical scaffolds may hold significant potential for combating drug-resistant bacteria. In this study, a series of benzoic acid derivatives featuring a tetraphenylethylene (TPE) core were designed to modulate their p<i>K</i><sub>a</sub> by incorporating various electron-donating and electron-withdrawing groups. This approach led to the development of a series of effective <i>Staphylococcus aureus</i> therapeutic agents. Among these compounds, the nitro-substituted tetraphenylethylene benzoic acid derivative (NOA) exhibits an ultralow minimum inhibitory concentration (MIC = 0.04 μg/mL) against <i>S. aureus</i>, while MIC of the traditional antibiotic vancomycin was 0.13 μg/mL. NOA achieved a 99% elimination rate of <i>S. aureus</i> at a 0.16 μg/mL and displayed antibacterial activity against <i>S. aureus</i> biofilm at 0.32 μg/mL. NOA could effectively treat wound infections caused by <i>S. aureus</i> in infected mouse models. This study provides valuable advice about the chemical substituents for designing new antibacterial agents.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2305–2316"},"PeriodicalIF":3.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184296","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":"Cysteine-Targeting Gd-Based Spin Label and Its Application in Electron Paramagnetic Resonance Spectroscopy","authors":"Xuemei Yao, , , Eliane Landwehr, , , Mian Qi, , , Miriam Hülsmann, , , Malte Drescher, , and , Adelheid Godt*, ","doi":"10.1021/acs.bioconjchem.5c00358","DOIUrl":"10.1021/acs.bioconjchem.5c00358","url":null,"abstract":"<p >Highly selective and fast reactions at the thiol group of a cysteine-containing peptide or protein, giving a reduction-resistant linkage, are highly desirable for anchoring a paramagnetic label that enables structure determination with electron paramagnetic resonance and/or nuclear magnetic resonance spectroscopy. One possibility is the Michael addition of the thiol group onto a 4-vinylpyridine, which is a structural subunit of the labeling agent, e.g., of the complex 4-vinyl-PyMTA-Gd. This reaction, however, turned out to be too slow for broad applicability. If pyridine is exchanged for pyrimidine, this reaction becomes very fast while still being sufficiently chemoselective, as is demonstrated with reactions of the complexes 4-vinyl-PymiMTA-Ln with Ln = Gd and/or La, which contain a 4-vinylpyrimidine subunit, with cysteine, cysteine-containing oligoproline, and cysteine-containing thioredoxin. Furthermore, it was found that the complex PymiMTA-Gd is a suitable spin label for distance determination via double electron electron resonance spectroscopy. Interestingly, the EPR spectra of PyMTA-Gd and PymiMTA-Gd and their relaxation times are very similar. Obviously, the exchange of pyridine for pyrimidine has little effect on these relevant EPR spectroscopical properties. This indicates that other pyridine-containing Gd<sup>3+</sup> complexes may be convertible in the same way to fast-reacting, ready-made spin labels while keeping their favorable EPR spectroscopical properties.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2267–2286"},"PeriodicalIF":3.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147132","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}
Nivedha Veerasubramanian, , , Anne Aalto, , and , Seraphine V. Wegner*,
{"title":"Light-Controlled Promiscuous Cell Adhesion through the Plasma Membrane-Binding Protein BcLOV4","authors":"Nivedha Veerasubramanian, , , Anne Aalto, , and , Seraphine V. Wegner*, ","doi":"10.1021/acs.bioconjchem.5c00304","DOIUrl":"10.1021/acs.bioconjchem.5c00304","url":null,"abstract":"<p >Dynamic regulation of cell–cell adhesion is fundamental to numerous biological processes and is the key to engineering multicellular structures. Optogenetic tools offer precise spatiotemporal control over cell–cell adhesions, but current methods often require the genetic modification of each participating cell type. To address this limitation, we engineered a single-component synthetic cell adhesion molecule based on the blue-light-responsive, plasma membrane-binding protein BcLOV4. We tagged BcLOV4 with a transmembrane domain to display it on the outer plasma membrane (BcLOV4-PM). Under blue light but not in the dark, BcLOV4-PM cells formed both homotypic adhesions with other BcLOV4-PM cells and heterotypic adhesions with a range of unmodified wild-type cells. While these adhesions were not reversed in the dark, they could be efficiently disrupted by increasing the temperature to 37 °C, leveraging BcLOV4’s thermosensitivity. Using BcLOV4-PM-based adhesions, we demonstrated light-controlled compaction of spheroids in both monocultures and cocultures with wild-type cells. Altogether, BcLOV4-PM enables promiscuous, modular, light-dependent control of cell–cell adhesions without requiring genetic modification of all cell types involved, offering promising applications in tissue engineering and the study of multicellular process.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2210–2219"},"PeriodicalIF":3.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111626","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}
Nicholas G. Horton, , , Jagandeep S. Saraya, , and , Derek K. O’Flaherty*,
{"title":"Novel Disulfide-Containing Linkages of Pyrimidine Nucleobases to Solid Supports: A Versatile Platform for Oligonucleotide Conjugation","authors":"Nicholas G. Horton, , , Jagandeep S. Saraya, , and , Derek K. O’Flaherty*, ","doi":"10.1021/acs.bioconjchem.5c00326","DOIUrl":"10.1021/acs.bioconjchem.5c00326","url":null,"abstract":"<p >Conjugation of ligands to oligonucleotides is a prominent strategy to enhance (bio)properties of nucleic acids such as cellular uptake/delivery, bioavailability, detection/tracking, and more. Here, we report a simple, cost-effective, and streamlined methodology for the incorporation of various conjugation handles into DNA and RNA. Pyrimidine nucleosides are linked to the solid support via a disulfide-containing linker covalently attached through the nucleobase, removing the typical sugar point-of-attachment requirement. We showcase a conjugation strategy in which nucleic acid strands can be permanently tagged with a ligand (via an azido group) and reversibly conjugated to another (via the linker containing a disulfide and primary amino group). Freed thiols can undergo further conjugation in certain constructs. Ultimately, our conjugation handles containing various orthogonal functional groups (e.g., azido, amino, and disulfide functional groups) will find applications in biotechnology and chemical biology.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2237–2246"},"PeriodicalIF":3.9,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111579","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}
Jian He, , , Dake Wen, , , Linv Xia*, , , Zhigang Hu*, , and , Kai Wang*,
{"title":"Molecular Imaging of Diabetes-Associated Glutathione S-Transferase Dysregulation Using a Smart Activatable Probe","authors":"Jian He, , , Dake Wen, , , Linv Xia*, , , Zhigang Hu*, , and , Kai Wang*, ","doi":"10.1021/acs.bioconjchem.5c00417","DOIUrl":"10.1021/acs.bioconjchem.5c00417","url":null,"abstract":"<p >We developed a dual-modal GSTP probe that exhibits GST-responsive fluorescence enhancement and photoacoustic signal reduction. GSTP demonstrated excellent selectivity, sensitivity, and biocompatibility. In diabetic mice, GSTP revealed a decreased level of hepatic GST activity partially restored by metformin treatment, supported by serum analysis and histopathological evaluation, highlighting its clinical translation potential for diabetes monitoring.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2298–2304"},"PeriodicalIF":3.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084563","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":"Membrane Protein-Binding and Membrane-Inserting Chimeras for Cancer Therapy","authors":"Jiamin Cai, , , Sujuan Wang, , , Aili Zhou, , , Dongchen Zhang, , , Fang Zhou*, , and , Zilong Zhao*, ","doi":"10.1021/acs.bioconjchem.5c00341","DOIUrl":"10.1021/acs.bioconjchem.5c00341","url":null,"abstract":"<p >High-efficiency molecular recognition tools, such as aptamers and antibodies, play a pivotal role in precise cancer theranostics. However, their noncovalent interactions with target molecules often limit their accumulation and retention within the tumor microenvironment. In this study, we introduce a class of membrane protein-targeting and membrane-inserting (MBI) chimeras, created by conjugating a membrane protein-targeting aptamer (as a model) with a pH-responsive membrane-inserting domain derived from the pH-Low Insertion Peptide (pHLIP). By harnessing the synergistic effects of these two distinct mechanisms, these MBI chimeras efficiently bind to tumor cells in the acidic microenvironment, enabling efficient delivery of chlorin e6 (Ce6) to the targeted cells. In vivo studies demonstrate that the Ce6-load MBI chimera, Sgc8-pHLIP, exhibits significantly enhanced photodynamic therapeutic efficacy compared to Ce6-loaded control constructs, which lack either membrane insertion functionality or specific membrane protein recognition. Overall, this work presents a promising strategy for the development of highly efficient molecular recognition tools for precise cancer therapeutics.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2116–2123"},"PeriodicalIF":3.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068638","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":"Recent Progress in Hydrogen Sulfide-Generating Nanomedicines for Cancer Therapy: From Design to In Situ Generation","authors":"Kaiyue Song, , , Xinlin Jia, , , Feng Zhao, , , Fen Liu, , , Cong Jiang*, , and , Xianglong Li*, ","doi":"10.1021/acs.bioconjchem.5c00318","DOIUrl":"10.1021/acs.bioconjchem.5c00318","url":null,"abstract":"<p >Hydrogen sulfide (H<sub>2</sub>S), once regarded solely as a toxic gas, has emerged as a star molecule for potential anticancer therapy. However, precise spatiotemporal control of H<sub>2</sub>S delivery remains challenging due to rapid diffusion and systemic toxicity risks. Recent advances in nanotechnology have enabled the design of H<sub>2</sub>S-generating nanomedicines (HSGNs) that address these limitations through stimuli-responsive in situ H<sub>2</sub>S generation. Through engineered design, HSGNs with different in situ generation mechanisms (such as pH and GSH responses) can be designed to improve the controlled release of H<sub>2</sub>S within cells effectively, and considerable efforts have been made to explore their multimodal synergistic effects in cancer therapy. This review systematically examines the development of HSGNs, focusing on material innovations, controlled-release strategies, and multimodal therapeutic applications in cancer treatment, and, finally, provides a prospective view of the future development of HSGNs to accelerate their practical clinical translation and application.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2091–2108"},"PeriodicalIF":3.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074135","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}
Wenlong Sun, , , Weining Weng, , , Jing Shi, , , Boyang Ma, , , Kelly D. DeMarco, , , Fu Gui, , , Rui Jin, , , Marcus Ruscetti, , , Li Jia, , , Wenhao Hu, , , Yu Shi*, , and , Xun Meng*,
{"title":"SPARC: A Multipayload ADC Architecture for Programmable Drug Combinations","authors":"Wenlong Sun, , , Weining Weng, , , Jing Shi, , , Boyang Ma, , , Kelly D. DeMarco, , , Fu Gui, , , Rui Jin, , , Marcus Ruscetti, , , Li Jia, , , Wenhao Hu, , , Yu Shi*, , and , Xun Meng*, ","doi":"10.1021/acs.bioconjchem.5c00239","DOIUrl":"10.1021/acs.bioconjchem.5c00239","url":null,"abstract":"<p >Drug combination is a cornerstone of modern medicine, particularly in oncology. However, drug combinations often fail due to poor disease site tropism and additive toxicities of composite drugs. Among targeted drug delivery systems for reducing toxicity, the antibody-drug conjugate (ADC) is effective for single cytotoxic payload delivery. Multipayload ADC for combination therapy is mostly limited to two chemotherapeutics at fixed ratios, hampered by a lack of payload combination synergy/toxicity knowledge and complex antibody engineering and linker chemistries. Here we design synergistic payload-antibody ratiometric conjugate (SPARC) based on an elucidation of payload ratio-dependent pharmacology and toxicology of drug combinations delivered by a previously described clinical-stage T1000-ADC linker. Multi-T1000 payload (MTP) moieties are synthesized through a convergent process by orthogonally linking two or more azide–alkyne-modified, clickable T1000 payloads. Direct conjugation of an MTP to a native antibody or combinatorial, sequential conjugation of two MTPs to engineered and native cysteines of THIOMABs leads to a programmable assembly of SPARCs with 2–6 payloads, a total drug antibody ratio (DAR) as high as 30, and a tunable payload ratio from 1 to 10. SPARCs are stable and homogeneous, and conjugation of multiple payloads does not affect antibody binding. SPARCs achieve a more precise pharmacological discrimination in vivo, with lower off-target additive toxicity due to reduced payload release compared to single-payload ADCs but higher efficacy in targeted cells by synergistic/additive interactions among pharmacokinetically synchronized payloads. SPARCs combining Topoisomerase I (TOP1) with DNA Damage Response (DDR) inhibitors outperform single-TOP1 ADCs and free-drug combinations. SPARCs also exhibit improved safety profiles with reduced hematological toxicity and synchronized payload pharmacokinetics. SPARC has the potential to usher in a new generation of ADCs by reusing abandoned drugs as deliverable payloads and represents a transformative approach to precision combination therapy, addressing unmet needs in oncology and other disease areas through programmable, rationally designed drug codelivery.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2158–2171"},"PeriodicalIF":3.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.5c00239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074130","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}
Jun Hyuk Lee, , , Hyeondo Lee, , , Yeonho Bae, , and , Hyejung Mok*,
{"title":"Bile Acid–Histidine Decapeptide Conjugates as Promising Additives in Lipid Nanoparticle Formulation for siRNA Delivery","authors":"Jun Hyuk Lee, , , Hyeondo Lee, , , Yeonho Bae, , and , Hyejung Mok*, ","doi":"10.1021/acs.bioconjchem.5c00303","DOIUrl":"10.1021/acs.bioconjchem.5c00303","url":null,"abstract":"<p >For siRNA-based therapeutics that require repeated administration, the accumulation of ionizable lipids in the body could cause <i>in vivo</i> safety issues. In the present study, we examined the feasibility of a bile acid–histidine decapeptide (H10) conjugate as a novel, biocompatible, and potential additive to reduce the proportion of ionizable lipids for the formulation of LNPs. A lithocholic acid (LCA)-H10 conjugate (LH conjugate) was synthesized and incorporated into the LNPs with low proportions of ionizable lipids (LiLNPs). The fabricated LH conjugate-containing LiLNPs (LiLNP-LH) exhibited more promising gene silencing activity than LiLNPs, despite their similar particle size and morphology. Additionally, LiLNP-LHs exhibited an elevated liver accumulation after intravenous injection and significantly decreased release of the inflammatory cytokines, compared with conventional LNPs with high proportions of ionizable lipids (HiLNPs). Thus, we successfully reduced the proportion of ionizable lipids in LNPs by adding LH conjugates, which could serve as carriers for diverse siRNA therapeutics with promising silencing activity and superior <i>in vivo</i> safety.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2197–2209"},"PeriodicalIF":3.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068631","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":"Functional Bioimaging Probes: Fluorescent Conjugated Polymer Nanoparticles Coupled with Pleural Fluid-Derived Peptides and Proteins","authors":"Kerem Tok, , , Hichem Moulahoum*, , , F. Baris Barlas, , , Oguzhan Karakurt, , , Nursima Ucar, , , Didem Aksu, , , Dilara Yeniterzi, , , Ozge Ozufuklar, , , Dilara Gürsoy, , , Saniye Soylemez, , , Emine Guler Celik, , , Ali Cirpan, , , Tevfik Ilker Akcam, , , Kutsal Turhan, , , Figen Zihnioglu, , and , Suna Timur*, ","doi":"10.1021/acs.bioconjchem.5c00321","DOIUrl":"10.1021/acs.bioconjchem.5c00321","url":null,"abstract":"<p >Thiol-functionalized conjugated polymers offer a versatile platform for designing fluorescent nanomaterials with biomedical relevance. In this study, a thiol modified conjugated polymer composed of benzoxadiazole (BO) and carbazole (POxC-SH) was synthesized, then converted into fluorescent nanoparticles (POxC-SH NPs) via a reprecipitation method. The nanoparticles exhibited strong photoluminescence, colloidal stability, and monodispersity in media. Surface thiol groups enabled conjugation with peptide and protein components isolated from the pleural fluid of lung adenocarcinoma patients using SMCC cross-linking. The resulting bioconjugated nanoprobe was characterized by spectroscopic methods, FTIR, XPS, and Mass spectrometry. Cellular studies in A549 and BEAS-2B cell lines demonstrated efficient internalization and low toxicity of both native and conjugated nanoparticles. This work presents a proof of concept for using thiol-modified conjugated polymer nanoparticles as intrinsically fluorescent, patient-adaptable imaging agents, bridging conjugated polymer chemistry with targeted biomedical applications.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"36 10","pages":"2220–2236"},"PeriodicalIF":3.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145051344","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}