Chemical Biology & Drug Design最新文献

{"title":"Procyanidin Alleviates Diabetic Retinopathy by Activating the Expression of Activating Transcription Factor 1 Expression to Upregulate Synoviolin 1 and Inhibit the High Mobility Group Box 1/Toll-Like Receptor 4 Pathway","authors":"Limin Zheng,&nbsp;Yaodan Cao,&nbsp;Wuyun Lu,&nbsp;Jinqi Hao,&nbsp;Yanqin Yu,&nbsp;Songtao Yuan","doi":"10.1111/cbdd.70174","DOIUrl":"https://doi.org/10.1111/cbdd.70174","url":null,"abstract":"<div>\u0000 \u0000 <p>Diabetic retinopathy (DR) remains a major cause of vision loss among working-age individuals, significantly impairing quality of life in diabetic patients. While no definitive cure exists, Procyanidin (PRO), a polyphenolic compound, has shown potential in mitigating diabetes-related complications. However, its mechanism of action in DR remains poorly understood. To explore this, we established an in vitro high glucose (HG) model using human retinal microvascular endothelial cells (hRMECs) and an in vivo diabetic rat model. Cells were cultured in normal glucose (NG, 5 mM) or HG (30 mM) for 48 h, followed by PRO treatment. Techniques including qRT-PCR, Western blotting, flow cytometry, histological staining, Transwell, tube formation, chromatin immunoprecipitation (ChIP), and dual-luciferase assays were employed. PRO treatment conferred protection against DR; however, this effect was reversed upon knockdown of activating transcription factor 1 (ATF1). Mechanistically, ATF1 enhanced transcription of synoviolin 1 (SYVN1), promoting HMGB1 degradation via ubiquitination and suppressing the HMGB1/toll-like receptor 4 (TLR4) signaling pathway. Findings from the in vitro model were validated in vivo. In conclusion, PRO alleviates DR by regulating the ATF1/SYVN1/HMGB1 axis and inhibiting pro-inflammatory signaling. These results provide novel insights into the molecular mechanism of PRO's protective role in DR and support its therapeutic potential.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145146611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond ATP Synthase Inhibition: Chemical Diversification, Bioactivities, and Therapeutic Potential of Oligomycin A","authors":"Mohamed S. Nafie,&nbsp;Muna A. Alshams,&nbsp;Mohamed K. Diab,&nbsp;Heba F. Ashour,&nbsp;Asmaa S. A. Yassen","doi":"10.1111/cbdd.70173","DOIUrl":"https://doi.org/10.1111/cbdd.70173","url":null,"abstract":"<div>\u0000 \u0000 <p>Oligomycin A, initially identified as a macrolide antibiotic and a mitochondrial ATP synthase inhibitor, has recently transitioned from a laboratory tool to a multifaceted agent with promising therapeutic and industrial applications. Its irreversible inhibition of the F₀ subunit interrupts ATP synthesis and informs about metabolic susceptibilities in neoplastic cells, such as the Warburg effect and reversal of multidrug resistance by P-glycoprotein inhibition. Guided by structural studies of its interaction with the c10-ring of ATP synthase, analogs like bedaquiline were rationally designed as antibacterial candidates, and the analog spiropiperidine derivatives were inspired by improving ischemia–reperfusion injury. Although this derivative has great potential, clinical translation is limited by systemic toxicity, poor solubility, and environmental persistence. Emerging approaches like PEGylation and combination therapies (e.g., with docetaxel) have started to address selectivity and off-target effects. There are still challenges in balancing efficacy, safety, and environmental impact. This review summarizes the current knowledge and mechanisms of action of oligomycin A and its derivatives that should be of interest in the design of bioactive agents with potential therapeutic applications. This is intended to serve as a motivator for moving forward with future research avenues toward optimizing Oligomycin A-based therapeutics to derive as much of the potential benefit as possible while mitigating the harms associated.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145146612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kisspeptin-10 Improves Gestational Diabetes Mellitus Symptoms in Rats by Suppressing Insulin Resistance in Placental Trophoblast Cells by Activating the Cyclic AMP/Protein Kinase A Pathway","authors":"Jianhua Li,&nbsp;Jinhuan Chen,&nbsp;Lin Lu,&nbsp;Bei Gan","doi":"10.1111/cbdd.70169","DOIUrl":"https://doi.org/10.1111/cbdd.70169","url":null,"abstract":"<div>\u0000 \u0000 <p>Gestational diabetes mellitus (GDM) is a common pregnancy complication that leads to insulin resistance (IR) and adversely affects both maternal and fetal health. Kisspeptin-10 (Kp-10), a peptide acting via G Protein-Coupled Receptor 54 (<i>Gpr54</i>), has shown potential in modulating insulin secretion, but its role in GDM remains unclear. This study explores Kp-10's therapeutic effects on GDM by targeting IR in placental tissues. We used GDM rat models (induced by a high-fat diet and streptozotocin) and high-glucose-treated HTR8/SVneo trophoblast cells to investigate Kp-10's effects on glucose metabolism, insulin signaling, and the cAMP/PKA pathway. Our results show that <i>Gpr54</i> expression was significantly downregulated in the placental tissues of GDM rats, which was associated with impaired glucose uptake and IR. Kp-10 treatment improved fasting blood glucose (FBG) levels, insulin sensitivity, and fetal outcomes, including increased fetal weight and decreased fetal blood glucose. Moreover, Kp-10 restored the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway and enhanced glucose uptake by upregulating <i>Glut</i>-<i>4</i>, <i>Insr</i>, and <i>Irs1</i> expression in both placental tissues and HTR8/SVneo cells. The effects of Kp-10 were reversed by the cAMP inhibitor SQ22536, confirming the involvement of the cAMP/PKA pathway in its anti-IR effects. Our findings suggest that Kp-10 has the potential as a therapeutic agent for alleviating IR in GDM and improving maternal–fetal outcomes.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Covalent and Modulable Inhibitor of the Tubulin-Microtubule System: Insights Into the Mechanism of Cacalol","authors":"Edgar López-López,&nbsp;José L. Medina-Franco,&nbsp;Eric Salinas-Arellano,&nbsp;Karen J. Ardila-Fierro,&nbsp;Julio C. Pardo-Novoa,&nbsp;Rosa E. del Río,&nbsp;Carlos M. Cerda-García-Rojas","doi":"10.1111/cbdd.70165","DOIUrl":"https://doi.org/10.1111/cbdd.70165","url":null,"abstract":"<p>Inhibitors of the tubulin-microtubule system are part of an effective strategy to treat different kinds of cancer, whose research has allowed scientists to discover and develop new and more selective molecules. Cacalol (<b>1</b>) is a natural product with anti-cancer activity and documented selectivity in breast cells, but with an undescribed molecular mechanism associated with these properties. The main objective of this work is to provide evidence that helps to explain the inhibitory and selective activity reported for cacalol (<b>1</b>) against cancer cell lines and to expand the knowledge about the mechanism of action involved in it. Cacalol derivatives were studied using reactivity approaches, tubulin polymerization assays, mass spectrometry, and molecular modeling techniques to decode the inhibitory binding mechanism. This work demonstrates that an oxidated form of cacalol, the methylenecyclohexadienone <b>2</b>, is generated in highly oxidant conditions, thus emulating the environment present in cancer cells. This species (<b>2</b>) is responsible for the inhibition of tubulin polymerization by promoting an irreversible binding interaction with the Cys347 in α-tubulin.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145037717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rationally Designed InhA Inhibitors: A Comparative Anti-Tubercular Activity Study of Sulfonate Esters of Isoniazid Hydrazones and Their Structurally Flexible Benzyl Analogues","authors":"Mukanda Gedeon Kadima,&nbsp;Sahil Mishra,&nbsp;Gobind Kumar,&nbsp;Pule Seboletswe,&nbsp;Françoise Roquet-Banères,&nbsp;Maëlle Foubert,&nbsp;Laurent Kremer,&nbsp;Rajshekhar Karpoormath,&nbsp;Parvesh Singh","doi":"10.1111/cbdd.70171","DOIUrl":"https://doi.org/10.1111/cbdd.70171","url":null,"abstract":"<p>Molecular hybridization of isoniazid with hydrophobic aromatic moieties represents a promising strategy for the development of novel anti-tubercular therapeutics. In this study, a series of hybrid molecules (<b>5a–i</b>) was synthesized by linking isoniazid with aromatic sulfonate esters via a hydrazone bridge. Molecular docking studies revealed that these compounds interact effectively with the catalytic triad of the InhA enzyme (Y158, F149, and K165), suggesting their potential as InhA inhibitors. To enhance molecular flexibility and improve binding interactions with both NADH and the catalytic residues, a second generation of derivatives (<b>8a–k</b>) was designed and synthesized. All synthesized compounds were structurally characterized using spectroscopic techniques, including nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (IR), and high-resolution mass spectrometry. As anticipated, these new compounds exhibited enhanced anti-tubercular activity compared to their precursors. Notably, compound <b>8b</b> demonstrated significant potency with an MIC of 0.078 μg/mL, approximately twofold more active than its precursor <b>5b</b> (MIC = 0.156 μg/mL) against <i>Mycobacterium tuberculosis</i> (Mtb). However, both generations of compounds (e.g., <b>5a, 5b, 8a, 8b, 8c</b>, and <b>8 k</b>) lost activity against INH-resistant <i>Mtb</i> strains harboring <i>katG</i> mutations. Importantly, no cytotoxicity was observed for these compounds in THP-1 human monocytic cells at a concentration of 10 μg/mL. The structural integrity of the lead compound 8b was confirmed via ¹H NMR stability studies. The ADME/T parameters (absorption, distribution, metabolism, excretion, and toxicity) were also explored to determine their drug likeness and safety profile. Collectively, these hybrid molecules present valuable scaffolds for further optimization in the pursuit of new anti-tubercular agents.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of Potential Inhibitors of N-Myristoyltransferase in Leishmania amazonensis: A Computational and Experimental Study","authors":"Mariana Sant’Anna Pereira Nicolau,&nbsp;Millena Almeida Resende,&nbsp;Cintia de Campos Chaves,&nbsp;Renata Santos Rodrigues,&nbsp;Veridiana de Melo Rodrigues,&nbsp;Nilson Nicolau-Junior,&nbsp;Kelly Aparecida Geraldo Yoneyama","doi":"10.1111/cbdd.70170","DOIUrl":"https://doi.org/10.1111/cbdd.70170","url":null,"abstract":"<p>Leishmaniasis, a disease caused by <i>Leishmania</i> parasites, poses a significant health threat globally, particularly in Latin America and Brazil. <i>Leishmania amazonensis</i> is an important species because it is associated with both cutaneous leishmaniasis and an atypical visceral form. Current treatments are hindered by toxicity, resistance, and high cost, driving the need for new therapeutic targets and drugs. N-myristoyltransferase (NMT) is an important anti-leishmanial target. N-myristoyltransferase (NMT) is an important target in <i>Leishmania</i> parasites, as it plays a crucial role in the process of myristoylation, a lipid modification that involves the attachment of myristate, a 14-carbon saturated fatty acid, to the N-terminus of specific proteins. In this work, a shape-based modeling approach was employed to identify potential NMT inhibitors in <i>Leishmania amazonensis</i>. Using a pyrazole sulphonamide as a reference ligand, a five-feature shape-based model was developed and validated. Virtual screening of the DIVERSet EXP and CL libraries (~1 million compounds) prioritized the top 500 ranked molecules per subset based on the TanimotoCombo score. Molecular docking studies identified the three highest-ranking compounds from each subset based on ChemPLP scores and docking pose consistency. Among the selected ligands, CL 54016012, EXP 6689657, and EXP 9226834 exhibited the most favorable binding interactions, with CL 54016012 forming stable hydrogen bonds with Tyr80, Tyr217, and Tyr345. Molecular dynamics (MD) simulations indicated that ligand binding did not significantly alter NMT structural stability, although variations in binding energy and hydrogen bond were observed. CL 54016012 demonstrated the highest docking score, optimal RMSD stability, and the lowest predicted IC50 value (19.81 μM), suggesting its potential as a lead compound. In vitro cytotoxicity assays revealed that CL 54016012, CL 74995016, and EXP 6689657 reduced <i>L. amazonensis</i> viability in a dose-dependent manner, placing them as promising candidates for further investigation in anti-leishmanial drug development.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70170","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145012397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Triazole-Linked Indole Derivatives as Potent Soluble Epoxy Hydrolase Inhibitors With Promising Anticancer Activity","authors":"Vijaykumar D. Nimbarte,&nbsp;Shreya S. Sonak,&nbsp;Sharda A. Ishwarkar,&nbsp;Bharat Rathod,&nbsp;Saiprem Nehlani","doi":"10.1111/cbdd.70164","DOIUrl":"https://doi.org/10.1111/cbdd.70164","url":null,"abstract":"<div>\u0000 \u0000 <p>A novel series of triazole-linked indole derivatives was designed, synthesized, and evaluated as soluble epoxide hydrolase inhibitors (sEHIs) for their potential anticancer activity. These compounds exhibit strong binding affinity within the hydrophobic pockets of sEH, with compounds 9a and 9b emerging as the most potent inhibitors, achieving IC₅₀ values of 0.270 ± 0.014 nM and 0.358 ± 0.03 nM, respectively, in vitro. In addition, both compounds display significant cytotoxic activity against HeLa cells, with IC₅₀ values of 5.366 ± 0.91 μM and 5.686 ± 0.73 μM, respectively. Molecular docking studies, using the 1ZD5 crystal structure, reveal key hydrogen bond interactions analogous to those observed with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), providing mechanistic insights into their inhibitory activity. Structure–activity relationship (SAR) analysis further informs the rational optimization of these derivatives for enhanced potency. Overall, these findings highlight triazole-linked indole derivatives as promising lead candidates for the development of sEH-targeted anticancer therapeutics.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144929825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computationally Driven Exploration of Novel bis-Thiadiazole Sulfonamides as Alzheimer's Enzyme Inhibitors: A DFT and Kinetic Perspective","authors":"Farman Ullah,&nbsp;Shoaib Khan,&nbsp;Tayyiaba Iqbal,&nbsp;Hamdy Kashtoh,&nbsp;Eman Alzahrani","doi":"10.1111/cbdd.70166","DOIUrl":"https://doi.org/10.1111/cbdd.70166","url":null,"abstract":"<div>\u0000 \u0000 <p>In this research work, <i>bis</i>-thiadiazole based sulfonamide hybrid analogues <b>(1–15)</b> were synthesized by a novel synthetic approach. Structural confirmation was accomplished through ¹HNMR, ¹³CNMR, and HREI-MS techniques. Further, these analogues were examined for their biological activities against AChE and BuChE (Alzheimer disease). These compounds have a diverse range of potency against targeted enzymes with inhibitory concentration ranges for AChE (2.80 ± 0.30–21.10 ± 0.10 μM) and for BuChE (3.20 ± 0.10–22.40 ± 0.70 μM), respectively. Compounds <b>4</b>, <b>9</b>, and <b>11</b> emerged as the potent compounds against targeted enzymes and have inhibitory concentrations lower than donepezil (IC₅₀ = 5.50 ± 0.10 and 6.10 ± 0.20 μM) used as a reference drug. In addition, versatile computational approaches were adopted to determine interactive properties (by molecular docking), electronic distribution and stability (through DFT calculations), and drug likeness characteristics (by ADMET predictions) of the synthesized potent scaffolds. Product confirmation was confirmed by thin layer chromatography.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 3","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydroxyalkyne–Bithiophene Derivatives: Synthesis and Antileishmanial Activity","authors":"Rayanne Regina Beltrame Machado,&nbsp;Deysiane Lima Salvador,&nbsp;Carla Maria Beraldi Gomes,&nbsp;Amanda Beatriz Kawano Bakoshi,&nbsp;Tânia Ueda-Nakamura,&nbsp;Sueli de Oliveira Silva,&nbsp;Celso Vataru Nakamura,&nbsp;Maria Helena Sarragiotto,&nbsp;Danielle Lazarin-Bidóia","doi":"10.1111/cbdd.70167","DOIUrl":"https://doi.org/10.1111/cbdd.70167","url":null,"abstract":"<p>Leishmaniasis is one of the most important neglected tropical diseases, prevalent in underdeveloped or developing countries, and new pharmacological agents for this disease are urgently needed. In this study, thiophene derivatives based on the natural product 5′-methyl-(5-[4-acetoxy-1-butynyl])-2,2′-bithiophene were synthesized and evaluated against promastigote forms of <i>Leishmania amazonensis</i>. The bithiophene <b>BT-1</b> was the most potent and selective synthetic compound toward the parasites, exhibiting IC₅₀ of 23.2 μM against promastigotes and CC₅₀ of 216.5 μM against macrophages, and its mechanism of action was determined through biochemical and ultrastructural analyses. An accumulation of lipid bodies, loss of cellular content, increased reactive oxygen species production and lipid peroxidation, damage to the plasma membrane, and mitochondrial depolarization were observed in <b>BT-1</b>-treated parasites. The results indicated that the death of <i>L. amazonensis</i> induced by <b>BT-1</b> occurred via destabilizing the parasite's redox homeostasis. Our results also showed that the synthesis based on the natural compound scaffold consisted of useful strategies to obtain new synthetic antileishmanial compounds.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144891697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morpholine-Facilitated Enrichment-Triggered Delivery of Carbon Monoxide to Lysosome: A Feasibility Study","authors":"Ravi Tripathi,&nbsp;Dongning Liu,&nbsp;Xiaoxiao Yang,&nbsp;Ce Yang,&nbsp;Wen Lu,&nbsp;Qiyue Mao,&nbsp;Binghe Wang","doi":"10.1111/cbdd.70168","DOIUrl":"https://doi.org/10.1111/cbdd.70168","url":null,"abstract":"<div>\u0000 \u0000 <p>Targeted delivery of carbon monoxide (CO) prodrugs holds important therapeutic potential for various applications. Along this line, we developed an enrichment-triggered release (ETR) approach for activating 2-component (a diene and a dienophile) CO prodrugs upon enrichment in the mitochondrion, giving a “one stone, two birds” approach. Herein, we aim to broaden the scope of application to targeted delivery to the lysosome. We tethered a CO prodrug pair, a diene and a dienophile, with morpholine, a lysosomal targeting moiety. Several analogs were synthesized to tune the second-order rate constants (<i>k</i>₂) to a desirable range. We chose two pairs of the prodrugs with different second-order rate constants (0.087 and 0.21 M⁻¹ s⁻¹) to further study their enrichment and CO release ability. For one pair, LC–MS experiments revealed &gt; 13-fold enrichment of the morpholine-conjugated CO prodrug pair compared to non-targeted controls in HeLa cells. Fluorescence studies demonstrated the same enrichment and co-localization of LysoTracker. For the second pair, conjugation with morpholine did not lead to improved enrichment in the lysosome. This study represents the first demonstration of lysosome-targeted delivery of CO. However, our findings also note the nonuniversal nature for a morpholine moiety to lead to lysosomal enrichment. The modest magnitude of enrichment also means that this method may only be applicable for targeted delivery of a highly potent drug.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"106 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144853783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}