Bioconjugate Chemistry最新文献

{"title":"Efficient 96-Well Plate Conjugation of Unnatural Amino Acid Building Blocks to DNA for DNA-Encoded Library Applications","authors":"Peter Blakskjær*,&nbsp;Tobias N. Hansen,&nbsp;Lars K. Petersen,&nbsp;Frank A. Sløk and Nils J. V. Hansen,&nbsp;","doi":"10.1021/acs.bioconjchem.6c00010","DOIUrl":"10.1021/acs.bioconjchem.6c00010","url":null,"abstract":"<p >Herein, we describe a robust 96-well plate workflow for high-throughput synthesis of building block–oligonucleotide conjugates for the synthesis of DNA-encoded libraries. Building blocks are Boc- and pNs-protected aminoesters, and the method allows consecutive ligation of codon oligonucleotides, ester hydrolysis, and conjugation in one pot. Results from using the two protection group strategies are discussed. Building blocks are conjugated using DMTMM to codon-specific PEG12-amino-modified oligonucleotides made from ligation. Conjugates are purified by HPLC, and all manipulations including precipitation of DNA are done in 96-well plates, reducing hands-on time.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"37 6","pages":"1115–1120"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147968672","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":"A Theranostic Study of 177Lu-Labeled Anti-ADAM9 Antibody for the Treatment of Triple-Negative Breast Cancer","authors":"Huayan Zhang,&nbsp;Mingming Tang,&nbsp;Xiaofei Hao,&nbsp;Binwei Lin,&nbsp;Huan Du,&nbsp;Hu Long,&nbsp;Jiangjiang Hu,&nbsp;Rui Luo,&nbsp;Wei Wu and Xiaobo Du*,&nbsp;","doi":"10.1021/acs.bioconjchem.6c00126","DOIUrl":"10.1021/acs.bioconjchem.6c00126","url":null,"abstract":"<p >Triple-negative breast cancer (TNBC) is highly aggressive with limited diagnostic and therapeutic options. ADAM9 is overexpressed in TNBC and may serve as a theranostic target. Therefore, this study aims to develop [¹⁷⁷Lu]Lu-DOTA-48HZ810, an ADAM9-targeted probe, and evaluate its targeting specificity, imaging capability, efficacy, and safety in TNBC models. ADAM9 expression in TNBC cells was assessed by flow cytometry, and the probe was constructed by conjugating ¹⁷⁷Lu to the ADAM9-specific antibody 48HZ810 via DOTA, after which binding specificity, affinity, and internalization were evaluated using radioligand binding, immunoreactive fraction, and internalization assays. In vivo targeting and pharmacokinetics were further analyzed by SPECT/CT imaging and biodistribution studies, while efficacy, safety, and mechanisms were assessed via tumor growth, body weight, survival, hematology, histopathology, and immunofluorescence. High ADAM9 expression was confirmed in BT-549 cells, and [¹⁷⁷Lu]Lu-DOTA-48HZ810 showed &gt;99% radiochemical purity and stability, high affinity (<i>K</i>_d: 3.75 ± 0.72 nmol/L), and specificity (Bmax: 422.5 ± 17.85 nmol). The tumor was clearly visualized at 72 h, with peak uptake at 96 h (8.56 ± 0.69%ID/g), and the probe significantly inhibited tumor growth (TGI: 46.04% vs antibody: 18.14%) and improved survival (70% vs antibody: 50% vs control: 0%), with no significant toxicity observed. The antitumor activity was mediated by DNA damage, apoptosis induction, and proliferation suppression. Overall, the first ADAM9-targeted theranostic probe, [¹⁷⁷Lu]Lu-DOTA-48HZ810, was successfully developed, demonstrating excellent tumor targeting, antitumor efficacy, and safety in TNBC models, and validating ADAM9 as a viable theranostic target.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"37 6","pages":"1210–1221"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.6c00126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147968662","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":"Preformulated, Shelf-Stable, Dendritic Cell-Targeting Nanogel mRNA Vaccine Delivery Platform","authors":"Amy E. Laturski,&nbsp;Verónica Durán,&nbsp;Bruce T. Schaar,&nbsp;Maria T. Dulay,&nbsp;Shirit Einav and Joseph M. DeSimone*,&nbsp;","doi":"10.1021/acs.bioconjchem.6c00069","DOIUrl":"10.1021/acs.bioconjchem.6c00069","url":null,"abstract":"<p >Current mRNA-based vaccine platforms are limited by complex fabrication, stringent cold-chain dependence, and off-target <i>in vivo</i> delivery, restricting their global accessibility and targeting precision. Here we show a modular mRNA delivery platform; our approach integrates inverse microemulsion-derived polymeric nanogels with adsorption-based mRNA loading and the capability for ligand-directed targeting to develop targeted reductively cleavable acrylate-based inverse microemulsion nanogels (TRAINs). By decoupling nanoparticle fabrication from mRNA loading, preformed TRAINs can be stockpiled and later combined with newly designed mRNA, enabling a plug-and-play strategy for rapid adaptation to emerging pathogens, which is particularly advantageous for pandemic preparedness. This architecture supports efficient mRNA association and robust cellular uptake and translation in HEK293T cells. TRAIN also enables postsynthetic surface functionalization; as a proof of concept, CD206-targeted TRAINs promoted selective delivery to antigen-presenting cells (APCs), producing sustained and localized protein expression in BALB/c mice and preferential mRNA delivery to myeloid APCs in heterogeneous human peripheral blood mononuclear cells. Together, these results demonstrate TRAINs as a surface-customizable, adsorption-based mRNA delivery platform with potential for APC-targeted vaccination and rapid, adaptable vaccine deployment.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"37 6","pages":"1172–1184"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.bioconjchem.6c00069","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148141920","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":"Conjugation of Dietary Carnosine to Phe-Leu Dipeptide Affords a Potent Inhibitor of Multifaceted Aβ-Induced Neurotoxicity","authors":"Kamaljot Singh,&nbsp;Nitesh Priyadarshi,&nbsp;Bhupesh Goyal*,&nbsp;Nitin Kumar Singhal* and Deepti Goyal*,&nbsp;","doi":"10.1021/acs.bioconjchem.5c00649","DOIUrl":"10.1021/acs.bioconjchem.5c00649","url":null,"abstract":"<p >Alzheimer’s disease (AD) is a chronic neurological disorder manifested by cognitive decline, amyloid-β (Aβ) fibrillation, synaptic dysfunction, and neuronal loss. Furthermore, metal ion dysregulation is implicated in Aβ aggregation, oxidative stress, and neuronal toxicity, thereby exacerbating neurodegeneration. Thus, highly versatile chemical entities with a synergistic effect targeting Aβ aggregation, disintegrate Aβ fibrils, and impede Aβ-Cu²⁺ interactions hold considerable therapeutic potential against AD. With this aim, a novel tetrapeptide <i>Car</i>FL (β<i>-</i>Ala–His–Phe–Leu) was rationally designed in this work by conjugating a natural dietary endogenous metal chelator, <i>Car</i>, with an Aβ fibrillation inhibitor (FL). Remarkably, <i>Car</i>FL prevented Aβ₄₂ aggregation and disaggregated the preformed Aβ₄₂ fibrils by 75.7 ± 3.8%. Notably, <i>Car</i>FL displayed significant inhibitory activity against Cu²⁺-induced Aβ₄₂ aggregation (83.6 ± 0.8%) and disaggregated preformed Aβ₄₂/Cu²⁺ fibrils by 85.6 ± 0.7%. <i>Car</i>FL binds with Cu²⁺ ions in 1:1 stoichiometry and sequesters Cu²⁺ from the Aβ₄₂/Cu²⁺ complex with a binding constant (<i>K</i>_a) of 2.9 × 10⁶ M^–1, which, in turn, blocked the Cu²⁺-catalyzed reactive oxygen species (ROS) production. Importantly, <i>Car</i>FL protected the PC12 cells from Aβ₄₂-mediated toxicity and has a sufficient safety profile as determined by cell viability assay. Furthermore, molecular dynamics (MD) simulations highlighted high-affinity binding (Δ<i>G</i>_fit = −11.94 ± 0.42 kcal/mol) of <i>Car</i>FL to the aggregation-prone regions [central hydrophobic core (CHC) and C-terminal] of Aβ₄₂ monomer (Aβ₄₂M) (PDB: 1IYT) with a noteworthy contribution of van der Waals interactions. Importantly, MD simulations depicted that <i>Car</i>FL blocked the conformational transitions in Aβ₄₂M to the aggregation-competent β-sheet structures, consistent with various biophysical studies depicting <i>Car</i>FL-mediated inhibition of Aβ₄₂ fibrillation and disaggregation of preformed fibrillar species. Interestingly, <i>Car</i>FL-mediated noteworthy rise in the helical content from 37.0 ± 1.8 to 54.5 ± 0.6% in Aβ₄₂M–Cu²⁺ depicts the prevention of Cu²⁺-induced Aβ₄₂ misfolding. To our knowledge, the present study for the first time depicts the synergistic potential of carnosine conjugated to FL as an inhibitor of multifaceted Aβ-induced cytotoxicity in AD.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"37 6","pages":"1137–1157"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147924757","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":"Orthogonal Acyl Acceptor Substrate Pairs and hQC Improve Sequential Ligation by Peptide Asparaginyl Ligases","authors":"Brendan W. J. Ng,&nbsp;Yiyin Xia,&nbsp;Thuy A. Tran and Chuan-Fa Liu*,&nbsp;","doi":"10.1021/acs.bioconjchem.6c00141","DOIUrl":"10.1021/acs.bioconjchem.6c00141","url":null,"abstract":"<p >As highly versatile enzymatic tools for bioconjugation, peptide asparaginyl ligases (PALs) catalyze ligation reactions at Asn/Asp residues through transpeptidation. While Asn-ligation is favored over Asp-ligation, their different pH requirements make it possible to use Asn- and Asp-ligations sequentially for conjugating multiple payloads onto a protein. However, because the protein substrate for sequential ligation contains both an acyl donor at the C-terminus and an acceptor at the N-terminus, it can undergo self-ligation, which leads to cyclized or dimerized side products. Furthermore, the significantly slower Asp-ligation step severely limits the efficiency of the sequential ligation scheme. Here, we report the design of orthogonal acyl acceptor substrates to eliminate cyclization or dimer formation of the protein substrate and the incorporation of human glutaminyl cyclase (hQC) to improve the efficiency of Asp-ligation by rendering it irreversible. As PAL-mediated Asp-ligations and hQC catalysis may require different operating conditions, we performed a pH scan experiment using short model peptide substrates and identified optimal Asp-ligation conditions with OaAEP1b-C247A and hQC at pH 7 that maximize ligation while minimizing unwanted hydrolysis. We further identified orthogonal dipeptide acceptor substrates differing in their ability to be processed by the PAL enzyme. Using the optimal conditions and orthogonal acceptor pair, we then demonstrated C-to-N sequential ligation by first attaching a fluorescein tag to anti-HER2 DARPin, followed by conjugation with anti-EGFR affibody without intermediatory protection/deprotection steps. This produced a fluorescent-labeled anti-EGFR and anti-HER2 bispecific protein that was functional when assessed in representative EGFR- and HER2-positive model cell lines (A431 and BT474). Our work highlights the versatility of PALs in bioconjugation with a wide range of protein sizes and presents a promising approach to producing multicomponent biologics for pharmacological applications.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"37 6","pages":"1231–1239"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148003851","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":"A Case Study on the Impact of Thermal Hydrolysis and Lactone Ring Opening of Linker-Payload on Drug-to-Antibody Ratio Determination in a Topoisomerase I Inhibitor-Based ADC","authors":"Keying Liang,&nbsp;Xiaotong Zhou,&nbsp;Henghui Li,&nbsp;Yimei Lu,&nbsp;Fuming Zhang,&nbsp;Junmei Zeng,&nbsp;Xuanxuan Zhou,&nbsp;Yiqian Li,&nbsp;Hilaire Yam Fung Cheung,&nbsp;Kyu-Sung Lee,&nbsp;Yujie Zhang*,&nbsp;April Xu* and Jing Song*,&nbsp;","doi":"10.1021/acs.bioconjchem.6c00140","DOIUrl":"10.1021/acs.bioconjchem.6c00140","url":null,"abstract":"<p >Accurate determination of the drug-antibody ratio (DAR) of an antibody-drug conjugate (ADC) requires multiple orthogonal analytical methods to ensure appropriate control of this critical quality attribute (CQA). This study presents the development considerations of two quality control (QC) methods: reversed-phase liquid chromatography (RP-HPLC) and hydrophobic interaction liquid chromatography (HIC-HPLC) to determine DAR of a topoisomerase I (TOP1) inhibitor-based ADC. We found that elevated column temperature used in the RP-HPLC method induced payload detachment from the linker, giving rise to characteristic shoulder peaks. This study systematically characterized the kinetics of this thermal hydrolysis process and elucidated its impact on DAR determination. To mitigate the underestimation of DAR by RP-HPLC, we developed an HIC-HPLC method and applied low-pH conditions for sample pretreatment, together with an optimized mobile phase, to suppress pH-dependent lactone ring opening of TOP1 inhibitors, thereby improving chromatographic resolution and DAR accuracy. Collectively, this study comprehensively evaluates the advantages and limitations of RP- and HIC-HPLC methods and provides guidance for future control strategies of ADC DAR.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"37 6","pages":"1222–1230"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154450","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":"Organelle-Targeted Photosensitizers for Enhanced Photodynamic Therapy of Cancer","authors":"Yunxue Xu,&nbsp;Wenlong Zeng,&nbsp;Renfa Liu* and Zhifei Dai*,&nbsp;","doi":"10.1021/acs.bioconjchem.6c00104","DOIUrl":"10.1021/acs.bioconjchem.6c00104","url":null,"abstract":"<p >Photodynamic therapy (PDT) efficacy is limited by the random intracellular distribution of conventional photosensitizers (PSs), as reactive oxygen species (ROS) have an extremely short half-life. Organelle-targeted PSs can enhance PDT efficacy by concentrating ROS at critical subcellular sites, yet systematic evaluation and comparison of different organelle targets using a uniform parent PS remain scarce. Herein, a panel of organelle-targeted PSs using pyropheophorbide a (Ppa) as the parent photosensitizer was synthesized via a facile amide condensation reaction, including mitochondria-targeted PS (Ppa-Mit), lysosome-targeted PS (Ppa-Lys), endoplasmic reticulum-targeted PS (Ppa-ER), and nucleus-targeted PS (Ppa-Nuc). These PSs retained the optical properties of parent Ppa and exhibited precise organelle localization. Ppa-Mit showed the highest cellular uptake and ROS generation, while Ppa-Lys displayed the strongest photocytotoxicity with the lowest IC50 (0.109 μM) against Panc02 cells. Flow cytometry confirmed that all PSs induced tumor cell death primarily via inducing cell apoptosis. Notably, in this study, lysosome-targeted Ppa (Ppa-Lys) exhibited the strongest photocytotoxicity among the four organelle-targeted PSs tested in Panc02 cells. This study demonstrates lysosomal-targeting modification of PSs as a universal and effective strategy to improve the antitumor efficacy of PDT, providing valuable insights for rational PS design.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"37 6","pages":"1200–1209"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148012575","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":"A Near-Infrared Fluorescent Molecular Rotor Conjugated with the Aβ Self-Assembly Core Sequence for Selective Imaging of Amyloid Plaques In Vivo","authors":"Hengheng Xue,&nbsp;Kunyi Wang,&nbsp;Mingguang Zhu,&nbsp;Guoyang Zhang,&nbsp;Zixuan Zhang,&nbsp;Yulong Jin* and Zhuo Wang*,&nbsp;","doi":"10.1021/acs.bioconjchem.6c00151","DOIUrl":"10.1021/acs.bioconjchem.6c00151","url":null,"abstract":"<p >Abnormal aggregation of amyloid-β (Aβ) is a key pathological hallmark of Alzheimer’s disease (AD), motivating the development of probes with high sensitivity and selectivity. Most existing fluorescent probes for Aβ₄₂ aggregates are based on molecular rotor scaffolds, typically incorporating <i>N</i>,<i>N</i>-dialkylaniline motifs. Such fluorescent molecular rotors, however, often exhibit a nonspecific response to the β-sheet-rich misfolded protein aggregates, limiting their specificity for Aβ plaque imaging in complex biological environments. Herein, we report a near-infrared (NIR) fluorescent molecular rotor-peptide conjugate, PITN-Pep, constructed by coupling a rotor fluorophore (PITN) with the core self-assembly sequence of Aβ to enable selective recognition of Aβ₄₂ aggregates <i>in vivo</i>. The rotor unit PITN displayed a NIR fluorescence turn-on response upon binding to Aβ₄₂ aggregates. Conjugation with the peptide ligand (KLVFF-Aib, abbreviated Pep) endowed PITN-Pep with enhanced binding affinity (<i>K</i>_d = 96.9 nM) and improved selectivity over other pathological aggregates, such as misfolded tau and α-synuclein. Furthermore, PITN-Pep enables sensitive detection of early stage Aβ₄₂ aggregation during fibrillization. Molecular docking and molecular dynamics simulations suggest that cooperative hydrogen bonding and van der Waals interactions stabilized the complex between PITN-Pep and Aβ₄₂ aggregates. <i>In vivo</i> imaging demonstrated effective blood-brain barrier (BBB) penetration and enhanced fluorescence signals in the brains of AD model mice, highlighting the potential of PITN-Pep as a selective tracer for Aβ plaques in AD research.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"37 6","pages":"1240–1248"},"PeriodicalIF":4.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040092","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":"Brain Targeted Drug Delivery: Overcoming the Blood–Brain Barrier for the Treatment of Central Nervous System Diseases","authors":"Yang Liu,&nbsp;, ,&nbsp;Huile Gao*,&nbsp;, ,&nbsp;Zhiqing Pang,&nbsp;, ,&nbsp;Jia Li,&nbsp;, and ,&nbsp;Zhifei Dai,&nbsp;","doi":"10.1021/acs.bioconjchem.6c00204","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.6c00204","url":null,"abstract":"","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"37 5","pages":"810–811"},"PeriodicalIF":3.9,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147967172","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":"Synovial Targeting and Redox-Triggered Release: A Dual Strategy in Peptide-Drug Conjugates for Rheumatoid Arthritis","authors":"Yuhe Yang,&nbsp;, ,&nbsp;Jiangyan Tang,&nbsp;, ,&nbsp;Chunxi Li,&nbsp;, ,&nbsp;Yuhuan Zhao,&nbsp;, ,&nbsp;Wenbo Mao,&nbsp;, ,&nbsp;Na Yan,&nbsp;, ,&nbsp;Sanhu Gou,&nbsp;, ,&nbsp;Yun Zhang,&nbsp;, ,&nbsp;Hui Liu*,&nbsp;, and ,&nbsp;Jingman Ni*,&nbsp;","doi":"10.1021/acs.bioconjchem.6c00143","DOIUrl":"10.1021/acs.bioconjchem.6c00143","url":null,"abstract":"<p >Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. To overcome the rapid clearance and systemic side effects of sinomenine (SIN), three critical components of peptide-drug conjugates (PDCs), including the targeting peptide, linker, and payload, were optimized, and two synovial homing peptide-sinomenine conjugates, SIN-SS-DRL and dSIN-SS-DRL, linked via reduction-sensitive disulfide bonds, were developed. Both new conjugates exhibited markedly improved plasma stability and demonstrated selective, glutathione-triggered release of SIN, with LC-MS confirming an accelerated and more complete release from the dual-disulfide conjugate. <i>In vitro</i>, they effectively suppressed pro-inflammatory cytokines, while <i>in vivo</i> studies in adjuvant-induced arthritis mice showed significant alleviation of joint inflammation and bone damage, with efficacy comparable to or exceeding methotrexate. These results highlight the potential of dual disulfide-linked PDCs as a promising targeted therapy for RA, integrating active synovial homing and passive redox-responsive release to achieve superior therapeutic outcomes with favorable safety profiles.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry","volume":"37 5","pages":"1035–1046"},"PeriodicalIF":3.9,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147757353","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}