Pub Date : 2024-07-06DOI: 10.1016/j.bmc.2024.117831
Jordan Cossu , Corinne Ravelet , Véronique Martel-Frachet , Eric Peyrin , Didier Boturyn
The CD20 antigen is a key target for several diseases including lymphoma and autoimmune diseases. For over 20 years, several monoclonal antibodies were developed to treat CD20-related disorders. As many therapeutic proteins, their clinical use is however limited due to their nature with a costly biotechnological procedure and side effects such as the production of anti-drug neutralizing antibodies. Nucleic acid aptamers have some advantages over mAbs and are currently investigated for clinical use. We herein report the selection of DNA aptamer by using a peptide-based CE-SELEX (Capillary Electrophoresis-Systematic Evolution of Ligands by Exponential Enrichment) method. It was demonstrated that these aptamers bind specifically a CD20-expressing human cell line, with Kd estimated from isothermal titration calorimetry experiments in the micromolar range. This study demonstrates that the CE-SELEX is suitable as alternative method to the conventional Cell-SELEX to discover new cell-targeting compounds.
{"title":"Peptide-based CE-SELEX enables convenient isolation of aptamers specifically recognizing CD20-expressing cells","authors":"Jordan Cossu , Corinne Ravelet , Véronique Martel-Frachet , Eric Peyrin , Didier Boturyn","doi":"10.1016/j.bmc.2024.117831","DOIUrl":"https://doi.org/10.1016/j.bmc.2024.117831","url":null,"abstract":"<div><p>The CD20 antigen is a key target for several diseases including lymphoma and autoimmune diseases. For over 20 years, several monoclonal antibodies were developed to treat CD20-related disorders. As many therapeutic proteins, their clinical use is however limited due to their nature with a costly biotechnological procedure and side effects such as the production of anti-drug neutralizing antibodies. Nucleic acid aptamers have some advantages over mAbs and are currently investigated for clinical use. We herein report the selection of DNA aptamer by using a peptide-based CE-SELEX (Capillary Electrophoresis-Systematic Evolution of Ligands by Exponential Enrichment) method. It was demonstrated that these aptamers bind specifically a CD20-expressing human cell line, with K<sub>d</sub> estimated from isothermal titration calorimetry experiments in the micromolar range. This study demonstrates that the CE-SELEX is suitable as alternative method to the conventional Cell-SELEX to discover new cell-targeting compounds.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002451/pdfft?md5=cf6de293b85520bc20bdc6527d0dda50&pid=1-s2.0-S0968089624002451-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141606905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05DOI: 10.1016/j.bmc.2024.117826
Ahmed H.E. Hassan , Yeonwoo Choi , Rium Kim , Hyeon Jeong Kim , Aya M. Almatary , Selwan M. El-Sayed , Yeongae Lee , Jong Kil Lee , Ki Duk Park , Yong Sup Lee
Design, synthesis, and biological evaluation of two series of O4′-benzyl-hispidol derivatives and the analogous corresponding O3′-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4′-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3′-benzyl derivatives series. The most potential compound 2e of O4′-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3′-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.
本文报告了两个系列的 O4′-苄基-双环醇衍生物和类似的相应 O3′-苄基衍生物的设计、合成和生物学评价,旨在开发具有抗神经炎活性的选择性单胺氧化酶-B 抑制剂。与 O3′-苄基衍生物系列相比,第一个 O4′-苄基-hispidol 衍生物系列提供了几种更具潜在活性的 MAO-B 抑制剂。最有潜力的 O4′-苄基衍生物化合物 2e 的 MAO-B IC50 值为 0.38 µM,选择性指数为 264;而最有潜力的 O3′-苄基衍生物化合物 3b 的 MAO-B IC50 值仅为 0.95,选择性指数为 105。对显示亚微摩尔活性的最活跃化合物进行进一步的细胞活力和诱导产生促神经炎症介质的评估证实,化合物 2e 是一种潜在的先导化合物,它能在 3 µM 浓度下显著抑制小胶质细胞 BV2 细胞产生神经炎症介质一氧化氮,而在 30 µM 以下不会产生明显的细胞毒性。硅学分子对接研究预测了与 MAO 酶的合理结合模式,并提供了分子水平的见解。总之,本报告将化合物 2e 作为一种潜在的先导化合物,用于开发潜在的多功能化合物。
{"title":"Synthesis and biological evaluation of O4′-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents","authors":"Ahmed H.E. Hassan , Yeonwoo Choi , Rium Kim , Hyeon Jeong Kim , Aya M. Almatary , Selwan M. El-Sayed , Yeongae Lee , Jong Kil Lee , Ki Duk Park , Yong Sup Lee","doi":"10.1016/j.bmc.2024.117826","DOIUrl":"https://doi.org/10.1016/j.bmc.2024.117826","url":null,"abstract":"<div><p>Design, synthesis, and biological evaluation of two series of O<sup>4′</sup>-benzyl-hispidol derivatives and the analogous corresponding O<sup>3′</sup>-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O<sup>4′</sup>-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O<sup>3′</sup>-benzyl derivatives series. The most potential compound 2e of O<sup>4′</sup>-benzyl derivatives elicited sub-micromolar MAO-B IC<sub>50</sub> of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O<sup>3′</sup>-benzyl derivatives showed only 0.95 MAO-B IC<sub>50</sub> and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141606857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-03DOI: 10.1016/j.bmc.2024.117829
Antonio Carrieri , Alexia Barbarossa , Modesto de Candia , Francesco Samarelli , Cosimo Damiano Altomare , Kinga Czarnota-Łydka , Sylwia Sudoł-Tałaj , Gniewomir Latacz , Jadwiga Handzlik , Leonardo Brunetti , Luca Piemontese , Francesco Limongelli , Giovanni Lentini , Alessia Carocci
In pharmaceutical science and drug design the versatility of the pyrrolidine scaffold relating to spatial arrangement, synthetic accessibility and pharmacological profile is a largely explored and most likely interesting one. Nonetheless, few evidences suggest the pivotal role of pyrrolidine as scaffold for multipotent agents in neurodegenerative diseases. We then challenged the enrolling in the field of Alzheimer disease of so far not ravelled targets of this chemical cliché with a structure based and computer-aided design strategy focusing on multi-target action, versatile synthesis as well as pharmacological safeness. To achieve these hits, ten enantiomeric pairs of compounds were obtained and tested, and the biological data will be here presented and discussed. Among the novel compounds, coumarin and sesamol scaffolds containing analogues resulted promising perspectives.
{"title":"Chiral pyrrolidines as multipotent agents in Alzheimer and neurodegenerative diseases","authors":"Antonio Carrieri , Alexia Barbarossa , Modesto de Candia , Francesco Samarelli , Cosimo Damiano Altomare , Kinga Czarnota-Łydka , Sylwia Sudoł-Tałaj , Gniewomir Latacz , Jadwiga Handzlik , Leonardo Brunetti , Luca Piemontese , Francesco Limongelli , Giovanni Lentini , Alessia Carocci","doi":"10.1016/j.bmc.2024.117829","DOIUrl":"10.1016/j.bmc.2024.117829","url":null,"abstract":"<div><p>In pharmaceutical science and drug design the versatility of the pyrrolidine scaffold relating to spatial arrangement, synthetic accessibility and pharmacological profile is a largely explored and most likely interesting one. Nonetheless, few evidences suggest the pivotal role of pyrrolidine as scaffold for multipotent agents in neurodegenerative diseases. We then challenged the enrolling in the field of Alzheimer disease of so far not ravelled targets of this chemical cliché with a structure based and computer-aided design strategy focusing on multi-target action, versatile synthesis as well as pharmacological safeness. To achieve these hits, ten enantiomeric pairs of compounds were obtained and tested, and the biological data will be here presented and discussed. Among the novel compounds, coumarin and sesamol scaffolds containing analogues resulted promising perspectives.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002438/pdfft?md5=f1a68b9d04ceec35053cf671326cabbf&pid=1-s2.0-S0968089624002438-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Histone deacetylase inhibitors (HDACis) show beneficial effects on different hematological malignancy subtypes. However, their impacts on treating solid tumors are still limited due to diverse resistance mechanisms. Recent studies have found that the feedback activation of BRD4-LIFR-JAK1-STAT3 pathway after HDACi incubation is a vital mechanism inducing resistance of specific solid tumor cells to HDACis. This review summarizes the recent development of multi-target HDACis that can concurrently block BRD4-LIFR-JAK1-STAT3 pathway. Moreover, our findings hope to shed novel lights on developing novel multi-target HDACis with reduced BRD4-LIFR-JAK1-STAT3-mediated drug resistance in some tumors.
{"title":"Research progress of multi-target HDAC inhibitors blocking the BRD4-LIFR-JAK1-STAT3 signaling pathway in the treatment of cancer","authors":"Shuting Jia , Yuye Jia , Sufang Liang , Liqiang Wu","doi":"10.1016/j.bmc.2024.117827","DOIUrl":"10.1016/j.bmc.2024.117827","url":null,"abstract":"<div><p>Histone deacetylase inhibitors (HDACis) show beneficial effects on different hematological malignancy subtypes. However, their impacts on treating solid tumors are still limited due to diverse resistance mechanisms. Recent studies have found that the feedback activation of BRD4-LIFR-JAK1-STAT3 pathway after HDACi incubation is a vital mechanism inducing resistance of specific solid tumor cells to HDACis. This review summarizes the recent development of multi-target HDACis that can concurrently block BRD4-LIFR-JAK1-STAT3 pathway. Moreover, our findings hope to shed novel lights on developing novel multi-target HDACis with reduced BRD4-LIFR-JAK1-STAT3-mediated drug resistance in some tumors.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-02DOI: 10.1016/j.bmc.2024.117828
Caili Luo , Anni Ren , Zixuan Jin , Jianxin Zhang , Wei Shi , Yue Zeng , Zhaojun Liu , Mengru Lu , Yajing Hou , Feng Tang , Wei Huang
The approval of Trodelvy® validates TROP2 as a druggable but challenging target for antibody-drug conjugates (ADCs) to treat metastatic triple-negative breast cancer (mTNBC). Here, based on the TROP2-targeted antibody sacituzumab, we designed and developed several site-specific ADC candidates, which employ MMAE (monomethyl auristatin E) as the toxin, via IgG glycoengineering or affinity-directed traceless conjugation. Systematic evaluation of these site-specific ADCs in homogeneity, hydrophilicity, stability, and antitumor efficiency was conducted. The results indicate that the site-specific ADCs gsADC 3b made from one-step glycoengineering exhibit good aggregation stability and in vivo efficacy, providing a new format of ADCs that target TROP2.
{"title":"Design and synthesis of novel site-specific antibody-drug conjugates that target TROP2","authors":"Caili Luo , Anni Ren , Zixuan Jin , Jianxin Zhang , Wei Shi , Yue Zeng , Zhaojun Liu , Mengru Lu , Yajing Hou , Feng Tang , Wei Huang","doi":"10.1016/j.bmc.2024.117828","DOIUrl":"10.1016/j.bmc.2024.117828","url":null,"abstract":"<div><p>The approval of Trodelvy® validates TROP2 as a druggable but challenging target for antibody-drug conjugates (ADCs) to treat metastatic triple-negative breast cancer (mTNBC). Here, based on the TROP2-targeted antibody sacituzumab, we designed and developed several site-specific ADC candidates, which employ MMAE (monomethyl auristatin E) as the toxin, via IgG glycoengineering or affinity-directed traceless conjugation. Systematic evaluation of these site-specific ADCs in homogeneity, hydrophilicity, stability, and antitumor efficiency was conducted. The results indicate that the site-specific ADCs <strong>gsADC 3b</strong> made from one-step glycoengineering exhibit good aggregation stability and <em>in vivo</em> efficacy, providing a new format of ADCs that target TROP2.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fluorescence lymph imaging with indocyanine green (ICG) is widely utilized as diagnostic tool for lymphatic diseases. While this technique offers numerous advantages, the kinetics of ICG at the injection site can pose challenges for a detailed diagnosis. In this study, we synthesized various ICG derivatives possessing cationic, anionic, or uncharged substituents and examined their photochemical properties, binding affinity to human serum albumin, as well as their correlation to pharmacokinetics in mice. The introduction of different substituents not only affected certain physiochemical properties, but also impacted the pharmacokinetics within the lymph nodes. Immunofluorescence imaging suggested that the extent of uptake of the ICG derivatives by phagocytic cells may affect the retention of the contrast ratios in the lymph nodes. These findings can provide new insights in the pharmacokinetics in lymphatic tissues, which could be useful for the development of novel fluorescent agents for lymph imaging.
{"title":"Investigation of the substituent effect of indocyanine green derivatives for lymph imaging","authors":"Naoya Ieda , Hideo Takakura , Hirotaka Maeta , Takayuki Ohira , Koki Tsuchiya , Kohei Nakajima , Mikako Ogawa","doi":"10.1016/j.bmc.2024.117824","DOIUrl":"10.1016/j.bmc.2024.117824","url":null,"abstract":"<div><p>Fluorescence lymph imaging with indocyanine green (ICG) is widely utilized as diagnostic tool for lymphatic diseases. While this technique offers numerous advantages, the kinetics of ICG at the injection site can pose challenges for a detailed diagnosis. In this study, we synthesized various ICG derivatives possessing cationic, anionic, or uncharged substituents and examined their photochemical properties, binding affinity to human serum albumin, as well as their correlation to pharmacokinetics in mice. The introduction of different substituents not only affected certain physiochemical properties, but also impacted the pharmacokinetics within the lymph nodes. Immunofluorescence imaging suggested that the extent of uptake of the ICG derivatives by phagocytic cells may affect the retention of the contrast ratios in the lymph nodes. These findings can provide new insights in the pharmacokinetics in lymphatic tissues, which could be useful for the development of novel fluorescent agents for lymph imaging.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-28DOI: 10.1016/j.bmc.2024.117823
Katharina Distler , Simone Maschauer , Eduard Neu , Harald Hübner , Jürgen Einsiedel , Olaf Prante , Peter Gmeiner
Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the in vivo imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound JH112 and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, [18F]KD23 and [18F]KD10. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The 19F-substituted analog KD23 showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand KD10 displayed similar Ki values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for [18F]KD23 and [18F]KD10, respectively, within 20 min. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue.
{"title":"Structure-guided discovery of orexin receptor-binding PET ligands","authors":"Katharina Distler , Simone Maschauer , Eduard Neu , Harald Hübner , Jürgen Einsiedel , Olaf Prante , Peter Gmeiner","doi":"10.1016/j.bmc.2024.117823","DOIUrl":"10.1016/j.bmc.2024.117823","url":null,"abstract":"<div><p>Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the <em>in vivo</em> imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound <strong>JH112</strong> and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD23</strong> and <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD10</strong>. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The <sup>19</sup>F-substituted analog <strong>KD23</strong> showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand <strong>KD10</strong> displayed similar K<sub>i</sub> values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD23</strong> and <strong>[</strong><sup><strong>18</strong></sup><strong>F]KD10</strong>, respectively, within 20 min. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002372/pdfft?md5=75ec1fd3067164f133332174cec97fa8&pid=1-s2.0-S0968089624002372-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-28DOI: 10.1016/j.bmc.2024.117825
Qiang Li , Mingxin Dong , Pu Chen
To date, the US Food and Drug Administration (FDA) has approved six small interfering RNA (siRNA) drugs: patisiran, givosiran, lumasiran, inclisiran, vutrisiran, and nedosiran, serving as compelling evidence of the promising potential of RNA interference (RNAi) therapeutics. The successful implementation of siRNA therapeutics is improved through a combination of various chemical modifications and diverse delivery approaches. The utilization of chemically modified siRNA at specific sites on either the sense strand (SS) or antisense strand (AS) has the potential to enhance resistance to ribozyme degradation, improve stability and specificity, and prolong the efficacy of drugs. Herein, we provide comprehensive analyses concerning the correlation between chemical modifications and structure-guided siRNA design. Various modifications, such as 2′-modifications, 2′,4′-dual modifications, non-canonical sugar modifications, and phosphonate mimics, are crucial for the activity of siRNA. We also emphasize the essential strategies for enhancing overhang stability, improving RISC loading efficacy and strand selection, reducing off-target effects, and discussing the future of targeted delivery.
{"title":"Advances in structural-guided modifications of siRNA","authors":"Qiang Li , Mingxin Dong , Pu Chen","doi":"10.1016/j.bmc.2024.117825","DOIUrl":"https://doi.org/10.1016/j.bmc.2024.117825","url":null,"abstract":"<div><p>To date, the US Food and Drug Administration (FDA) has approved six small interfering RNA (siRNA) drugs: patisiran, givosiran, lumasiran, inclisiran, vutrisiran, and nedosiran, serving as compelling evidence of the promising potential of RNA interference (RNAi) therapeutics. The successful implementation of siRNA therapeutics is improved through a combination of various chemical modifications and diverse delivery approaches. The utilization of chemically modified siRNA at specific sites on either the sense strand (SS) or antisense strand (AS) has the potential to enhance resistance to ribozyme degradation, improve stability and specificity, and prolong the efficacy of drugs. Herein, we provide comprehensive analyses concerning the correlation between chemical modifications and structure-guided siRNA design. Various modifications, such as 2′-modifications, 2′,4′-dual modifications, non-canonical sugar modifications, and phosphonate mimics, are crucial for the activity of siRNA. We also emphasize the essential strategies for enhancing overhang stability, improving RISC loading efficacy and strand selection, reducing off-target effects, and discussing the future of targeted delivery.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141486998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The adenylation (A) domain of non-ribosomal peptide synthetases (NRPSs) catalyzes the adenylation reaction with substrate amino acids and ATP. Leveraging the distinct substrate specificity of A-domains, we previously developed photoaffinity probes for A-domains based on derivatization with a 5′-O-N-(aminoacyl)sulfamoyl adenosine (aminoacyl-AMS)-appended clickable benzophenone. Although our photoaffinity probes with different amino acid warheads enabled selective detection, visualization, and enrichment of target A-domains in proteomic environments, the effects of photoaffinity linkers have not been investigated. To explore the optimal benzophenone-based linker scaffold, we designed seven photoaffinity probes for the A-domains with different lengths, positions, and molecular shapes. Using probes 2–8 for the phenylalanine-activating A-domain of gramicidin S synthetase A (GrsA), we systematically investigated the binding affinity and labeling efficiency of the endogenous enzyme in a live producer cell. Our results indicated that the labeling efficiencies of probes 2–8 tended to depend on their binding affinities rather than on the linker length, flexibility, or position of the photoaffinity group. We also identified that probe 2 with a 4,4′-diaminobenzophenone linker exhibits the highest labeling efficiency for GrsA with fewer non-target labeling properties in live cells.
非核糖体肽合成酶(NRPSs)的腺苷酸化(A)结构域催化底物氨基酸和 ATP 的腺苷酸化反应。利用 A 结构域独特的底物特异性,我们先前开发出了基于 5'-O-N- (氨基酰)氨基磺酰基腺苷(aminoacyl-AMS)衍生化的 A 结构域光亲和探针。虽然我们的光亲和探针带有不同的氨基酸弹头,能够在蛋白质组环境中选择性地检测、显像和富集目标 A-结构域,但光亲和连接物的影响尚未得到研究。为了探索基于二苯甲酮的最佳连接剂支架,我们设计了七种不同长度、位置和分子形状的光亲和探针。我们使用针对绣线菊素 S 合成酶 A(GrsA)苯丙氨酸激活 A 结构域的探针 2-8 系统地研究了活体生产细胞中内源酶的结合亲和力和标记效率。结果表明,探针 2-8 的标记效率往往取决于它们的结合亲和力,而不是链接长度、灵活性或光亲和基团的位置。我们还发现,带有 4,4'-二氨基二苯甲酮连接体的探针 2 对 GrsA 的标记效率最高,而且在活细胞中的非目标标记特性较少。
{"title":"Probing for optimal photoaffinity linkers of benzophenone-based photoaffinity probes for adenylating enzymes","authors":"Sho Konno , Fumihiro Ishikawa , Hideaki Kakeya , Genzoh Tanabe","doi":"10.1016/j.bmc.2024.117815","DOIUrl":"10.1016/j.bmc.2024.117815","url":null,"abstract":"<div><p>The adenylation (A) domain of non-ribosomal peptide synthetases (NRPSs) catalyzes the adenylation reaction with substrate amino acids and ATP. Leveraging the distinct substrate specificity of A-domains, we previously developed photoaffinity probes for A-domains based on derivatization with a 5′-<em>O</em>-<em>N</em>-(aminoacyl)sulfamoyl adenosine (aminoacyl-AMS)-appended clickable benzophenone. Although our photoaffinity probes with different amino acid warheads enabled selective detection, visualization, and enrichment of target A-domains in proteomic environments, the effects of photoaffinity linkers have not been investigated. To explore the optimal benzophenone-based linker scaffold, we designed seven photoaffinity probes for the A-domains with different lengths, positions, and molecular shapes. Using probes <strong>2</strong>–<strong>8</strong> for the phenylalanine-activating A-domain of gramicidin S synthetase A (GrsA), we systematically investigated the binding affinity and labeling efficiency of the endogenous enzyme in a live producer cell. Our results indicated that the labeling efficiencies of probes <strong>2</strong>–<strong>8</strong> tended to depend on their binding affinities rather than on the linker length, flexibility, or position of the photoaffinity group. We also identified that probe <strong>2</strong> with a 4,4′-diaminobenzophenone linker exhibits the highest labeling efficiency for GrsA with fewer non-target labeling properties in live cells.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141464759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oligonucleotide therapeutics, particularly antisense oligonucleotides (ASOs), have emerged as promising candidates in drug discovery. However, their effective delivery to the target tissues and cells remains a challenge, necessitating the development of suitable drug delivery technologies for ASOs to enable their practical application. In this study, we synthesized a library of chemically modified dipeptide-ASO conjugates using a recent synthetic method based on the Ugi reaction. We then conducted in vitro screening of this library using luciferase-expressing cell lines to identify ligands capable of enhancing ASO activity. Our findings suggest that N-(4-nitrophenoxycarbonyl)glycine may interact with the thiophosphate moiety of the phosphorothioate-modification in ASO. Through our screening efforts, we identified two ligands that modestly reduced luciferase luminescence in a cell type-selective manner. Furthermore, quantification of luciferase mRNA levels revealed that one of these promising dipeptide-ASO conjugates markedly suppressed luciferase RNA levels through its antisense effect in prostate-derived DU-145 cells compared to the ASOs without ligand modification.
{"title":"In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity","authors":"Takashi Osawa , Ryosuke Kita , Yuuya Kasahara , Harumi Yamaguma , Taisuke Nakayama , Haruhiko Kamada , Satoshi Obika","doi":"10.1016/j.bmc.2024.117814","DOIUrl":"10.1016/j.bmc.2024.117814","url":null,"abstract":"<div><p>Oligonucleotide therapeutics, particularly antisense oligonucleotides (ASOs), have emerged as promising candidates in drug discovery. However, their effective delivery to the target tissues and cells remains a challenge, necessitating the development of suitable drug delivery technologies for ASOs to enable their practical application. In this study, we synthesized a library of chemically modified dipeptide-ASO conjugates using a recent synthetic method based on the Ugi reaction. We then conducted <em>in vitro</em> screening of this library using luciferase-expressing cell lines to identify ligands capable of enhancing ASO activity. Our findings suggest that <em>N</em>-(4-nitrophenoxycarbonyl)glycine may interact with the thiophosphate moiety of the phosphorothioate-modification in ASO. Through our screening efforts, we identified two ligands that modestly reduced luciferase luminescence in a cell type-selective manner. Furthermore, quantification of luciferase mRNA levels revealed that one of these promising dipeptide-ASO conjugates markedly suppressed luciferase RNA levels through its antisense effect in prostate-derived DU-145 cells compared to the ASOs without ligand modification.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002281/pdfft?md5=7c74d399586a23d991a8c4024ebec636&pid=1-s2.0-S0968089624002281-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}