ACS Bio & Med Chem Au最新文献

{"title":"A Bioluminescent Probe for H2S Detection in Tumor Microenvironment","authors":"Kang Lu,&nbsp;Yixian Wang,&nbsp;Chenhang Wang,&nbsp;Rui Liu,&nbsp;Kaiqiang Yang,&nbsp;Xuanchenye Zhang and Han Xiao*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0010210.1021/acsbiomedchemau.4c00102","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00102https://doi.org/10.1021/acsbiomedchemau.4c00102","url":null,"abstract":"<p >Hydrogen sulfide (H₂S) is an endogenous gaseous signaling molecule that regulates various physiological functions, and its abnormal levels have been closely linked to the onset and progression of numerous diseases including renal cell carcinoma (RCC). RCC is the most common malignant tumor of the kidney, accounting for 85–90% of all kidney cancer cases. However, studies using H₂S as a biomarker for monitoring RCC progression at the molecular level remain relatively limited. Most current H₂S luminescent probes suffer from low sensitivity and often need external stimuli, such as cysteine, to artificially elevate H₂S levels, thereby reducing their effectiveness in detecting H₂S in cells or in vivo. Although bioluminescent imaging probes are gaining attention for their specificity and high signal-to-noise ratio, no existing probes are specifically designed for detecting H₂S in RCC. Additionally, many bioluminescent probes face challenges such as short emission wavelengths or dependence on complex conditions such as external adenosine triphosphate (ATP). Herein, through “caging” the luciferin substrate QTZ with H₂S recognition groups, a H₂S-sensitive bioluminescent probe QTZ-N₃ with good sensitivity (∼0.19 μM) and selectivity was prepared. QTZ-N₃ can effectively detect endogenous H₂S in 786-O-Nluc renal cancer cells and sensitively monitor H₂S levels in the RCC xenograft nude mouse model without requiring stimuli like cysteine. Furthermore, QTZ-N₃ allows for the real-time monitoring of H₂S during tumor progression. This work lays a solid foundation for future understanding of the biological functions of H₂S in vivo.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"175–183 175–183"},"PeriodicalIF":3.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Terminator: A Software Package for Fast and Local Optimization of His-Tag Placement for Protein Affinity Purification.","authors":"Rokas Gerulskis, Shelley D Minteer","doi":"10.1021/acsbiomedchemau.4c00055","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00055","url":null,"abstract":"<p><p>Although the use of affinity tags can greatly improve purification of expressed enzymes, the placement of affinity tags can significantly impact the expression, solubility, and function of recombinant proteins. To facilitate the optimal design of 6xHis-tagged constructs for protein purification, we developed Terminator, a Python-based software package, which takes a UniProt ID or existing protein sequence as input, identifies related sequences, maps sequence conservation retrieved from ConSurf onto protein 3D structures retrieved from the PDB and SWISS-MODEL, and analyzes proximity to cavities and functional sites to recommend the N- or C-terminus for placement of 6xHis fusion tags <15 residues in length. The package also outputs a document with available purification and activity literature for the target and closely related proteins organized by year. Comparative analysis of Terminator predictions against published experimental tag behavior for 6xHis fusion tags <15 residues in length demonstrates an 86-100% accuracy in predicting the relative risk of ill effects between termini and a 92-93% accuracy in predicting the absolute risk of modifying individual termini. This reliability of Terminator's analysis suggests that proximity to surface cavities, not burial of wild-type termini, is the most reliable predictor of ill effects arising from short 6xHis fusion tags. This tool aims to expedite construct design and enhance the successful production of well-behaved proteins for studies in enzymology and biocatalysis with minimal need for computational resources, programming knowledge, or familiarity with protein-tag interference mechanisms.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"55-65"},"PeriodicalIF":3.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Terminator: A Software Package for Fast and Local Optimization of His-Tag Placement for Protein Affinity Purification","authors":"Rokas Gerulskis,&nbsp; and ,&nbsp;Shelley D. Minteer*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0005510.1021/acsbiomedchemau.4c00055","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00055https://doi.org/10.1021/acsbiomedchemau.4c00055","url":null,"abstract":"<p >Although the use of affinity tags can greatly improve purification of expressed enzymes, the placement of affinity tags can significantly impact the expression, solubility, and function of recombinant proteins. To facilitate the optimal design of 6xHis-tagged constructs for protein purification, we developed Terminator, a Python-based software package, which takes a UniProt ID or existing protein sequence as input, identifies related sequences, maps sequence conservation retrieved from ConSurf onto protein 3D structures retrieved from the PDB and SWISS-MODEL, and analyzes proximity to cavities and functional sites to recommend the N- or C-terminus for placement of 6xHis fusion tags &lt;15 residues in length. The package also outputs a document with available purification and activity literature for the target and closely related proteins organized by year. Comparative analysis of Terminator predictions against published experimental tag behavior for 6xHis fusion tags &lt;15 residues in length demonstrates an 86–100% accuracy in predicting the relative risk of ill effects between termini and a 92–93% accuracy in predicting the absolute risk of modifying individual termini. This reliability of Terminator’s analysis suggests that proximity to surface cavities, not burial of wild-type termini, is the most reliable predictor of ill effects arising from short 6xHis fusion tags. This tool aims to expedite construct design and enhance the successful production of well-behaved proteins for studies in enzymology and biocatalysis with minimal need for computational resources, programming knowledge, or familiarity with protein-tag interference mechanisms.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"55–65 55–65"},"PeriodicalIF":3.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Bioluminescent Probe for H₂S Detection in Tumor Microenvironment.","authors":"Kang Lu, Yixian Wang, Chenhang Wang, Rui Liu, Kaiqiang Yang, Xuanchenye Zhang, Han Xiao","doi":"10.1021/acsbiomedchemau.4c00102","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00102","url":null,"abstract":"<p><p>Hydrogen sulfide (H₂S) is an endogenous gaseous signaling molecule that regulates various physiological functions, and its abnormal levels have been closely linked to the onset and progression of numerous diseases including renal cell carcinoma (RCC). RCC is the most common malignant tumor of the kidney, accounting for 85-90% of all kidney cancer cases. However, studies using H₂S as a biomarker for monitoring RCC progression at the molecular level remain relatively limited. Most current H₂S luminescent probes suffer from low sensitivity and often need external stimuli, such as cysteine, to artificially elevate H₂S levels, thereby reducing their effectiveness in detecting H₂S in cells or in vivo. Although bioluminescent imaging probes are gaining attention for their specificity and high signal-to-noise ratio, no existing probes are specifically designed for detecting H₂S in RCC. Additionally, many bioluminescent probes face challenges such as short emission wavelengths or dependence on complex conditions such as external adenosine triphosphate (ATP). Herein, through \"caging\" the luciferin substrate QTZ with H₂S recognition groups, a H₂S-sensitive bioluminescent probe QTZ-N₃ with good sensitivity (∼0.19 μM) and selectivity was prepared. QTZ-N₃ can effectively detect endogenous H₂S in 786-O-Nluc renal cancer cells and sensitively monitor H₂S levels in the RCC xenograft nude mouse model without requiring stimuli like cysteine. Furthermore, QTZ-N₃ allows for the real-time monitoring of H₂S during tumor progression. This work lays a solid foundation for future understanding of the biological functions of H₂S in vivo.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"175-183"},"PeriodicalIF":3.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NIR-Responsive Black Phosphorus Nanosheet-Integrated Niosomes for Combinatorial Chemo-phototherapy of Cancers","authors":"Rahul Kumar,&nbsp;Shubham Kumar Singh,&nbsp;Rishabh Kumar Srivastava,&nbsp;Subhrajyoti Mallick and Raviraj Vankayala*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0008610.1021/acsbiomedchemau.4c00086","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00086https://doi.org/10.1021/acsbiomedchemau.4c00086","url":null,"abstract":"<p >Cancer remains one of the major challenges in the field of clinical biomedicine. There is a great deal of scope for the development of various innovative therapies. To advance in the field of cancer therapeutics, the research trend has gradually shifted to the development of biocompatible, controlled, and stable carrier systems. To address such issues, herein, we report NIR-responsive black phosphorus (BP) nanosheet-integrated niosomes to mediate chemo-phototherapy of cancers. Niosome-coated black phosphorus nanosheets loaded with indocyanine green (ICG) and doxorubicin (DOX) (NBID) exhibit very high drug loading efficiency (&gt;90%). Upon 808 nm NIR light irradiation, the NBID system initiates combinatorial effects where heat generation induced from BP nanosheets and ICG disrupts the niosomal coating, facilitating the controlled release of ICG and DOX in a pH- and light dual-responsive manner. This combinatorial approach induces DNA damage in cancer cells via DOX and also triggers photothermal (PTT) and photodynamic (PDT) effects, significantly enhancing tumor eradication. In a 2D cell culture model, the NBID formulation demonstrates excellent cytocompatibility in the dark, effective tumor cell uptake, and tumor cell death, showing potential for further application. To mimic the cancer microenvironment even more closely, the NBID nanoformulation has been tested against the 3D tumor spheroids, where NBID formulation shows tumor uptake and causes cancer cell death. The therapeutic efficacy of the NBID system can be controlled by laser, proving its light-responsive behavior to kill cancer cells in vitro. This integrated approach using NBID as a potent platform for combinatorial cancer therapy offers a promising advancement in achieving a safer, controlled, and stable drug delivery system.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"143–153 143–153"},"PeriodicalIF":3.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NIR-Responsive Black Phosphorus Nanosheet-Integrated Niosomes for Combinatorial Chemo-phototherapy of Cancers.","authors":"Rahul Kumar, Shubham Kumar Singh, Rishabh Kumar Srivastava, Subhrajyoti Mallick, Raviraj Vankayala","doi":"10.1021/acsbiomedchemau.4c00086","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00086","url":null,"abstract":"<p><p>Cancer remains one of the major challenges in the field of clinical biomedicine. There is a great deal of scope for the development of various innovative therapies. To advance in the field of cancer therapeutics, the research trend has gradually shifted to the development of biocompatible, controlled, and stable carrier systems. To address such issues, herein, we report NIR-responsive black phosphorus (BP) nanosheet-integrated niosomes to mediate chemo-phototherapy of cancers. Niosome-coated black phosphorus nanosheets loaded with indocyanine green (ICG) and doxorubicin (DOX) (NBID) exhibit very high drug loading efficiency (>90%). Upon 808 nm NIR light irradiation, the NBID system initiates combinatorial effects where heat generation induced from BP nanosheets and ICG disrupts the niosomal coating, facilitating the controlled release of ICG and DOX in a pH- and light dual-responsive manner. This combinatorial approach induces DNA damage in cancer cells via DOX and also triggers photothermal (PTT) and photodynamic (PDT) effects, significantly enhancing tumor eradication. In a 2D cell culture model, the NBID formulation demonstrates excellent cytocompatibility in the dark, effective tumor cell uptake, and tumor cell death, showing potential for further application. To mimic the cancer microenvironment even more closely, the NBID nanoformulation has been tested against the 3D tumor spheroids, where NBID formulation shows tumor uptake and causes cancer cell death. The therapeutic efficacy of the NBID system can be controlled by laser, proving its light-responsive behavior to kill cancer cells in vitro. This integrated approach using NBID as a potent platform for combinatorial cancer therapy offers a promising advancement in achieving a safer, controlled, and stable drug delivery system.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"143-153"},"PeriodicalIF":3.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Genetically Encoded Fluorescent Biosensor for Intracellular Measurement of Malonyl-CoA.","authors":"Brodie L Ranzau, Tiffany D Robinson, Jack M Scully, Edmund D Kapelczak, Teagan S Dean, Tara TeSlaa, Danielle L Schmitt","doi":"10.1021/acsbiomedchemau.4c00103","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00103","url":null,"abstract":"<p><p>Malonyl-CoA is the essential building block of fatty acids and regulates cell function through protein malonylation and allosteric regulation of signaling networks. Accordingly, the production and use of malonyl-CoA is finely tuned by the cellular energy status. Most studies of malonyl-CoA dynamics rely on bulk approaches that take only a snapshot of the average metabolic state of a population of cells, missing out on heterogeneous differences in malonyl-CoA and fatty acid biosynthesis that could be occurring among a cell population. To overcome this limitation, we have developed a genetically encoded fluorescent protein-based biosensor for malonyl-CoA that can be used to capture malonyl-CoA dynamics in single cells. This biosensor, termed Malibu (<b>mal</b>onyl-CoA <b>i</b>ntracellular <b>b</b>iosensor to <b>u</b>nderstand dynamics), exhibits an excitation-ratiometric change in response to malonyl-CoA binding. We first used Malibu to monitor malonyl-CoA dynamics during inhibition of fatty acid biosynthesis using cerulenin in <i>Escherichia coli</i>, observing an increase in Malibu response in a time- and dose-dependent manner. In HeLa cells, we used Malibu to monitor the impact of fatty acid biosynthesis inhibition on malonyl-CoA dynamics in single cells, finding that two inhibitors of fatty acid biosynthesis, cerulenin and orlistat, which inhibit different steps of fatty acid biosynthesis, increase malonyl-CoA levels. Altogether, we have developed a new genetically encoded biosensor for malonyl-CoA, which can be used to study malonyl-CoA dynamics in single cells, providing an unparalleled view into fatty acid biosynthesis.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"184-193"},"PeriodicalIF":3.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nucleic Acid Conjugates: Unlocking Therapeutic Potential.","authors":"Disha Kashyap, Michael J Booth","doi":"10.1021/acsbiomedchemau.4c00092","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00092","url":null,"abstract":"<p><p>Nucleic acids have emerged as a powerful class of therapeutics. Through simple base pair complementarity, nucleic acids allow the targeting of a variety of pathologically relevant proteins and RNA molecules. However, despite the preliminary successes of nucleic acids as drugs in the clinic, limited biodistribution, inadequate delivery mechanisms, and target engagement remain key challenges in the field. A key area of research has been the chemical optimization of nucleic acid backbones to significantly enhance their \"drug-like\" properties. Alternatively, this review focuses on the next generation of nucleic acid chemical modifications: covalent biochemical conjugates. These conjugates are being applied to improve the delivery, functionality, and targeting. Exploiting research on heterobifunctionals, such as PROTACs, RIBOTACs, molecular glues, etc., has the potential to dramatically expand nucleic acid drug functionality and target engagement capabilities. Such next-generation chemistry-based enhancements have the potential to unlock nucleic acids as effective and versatile therapeutic agents.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"3-15"},"PeriodicalIF":3.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Genetically Encoded Fluorescent Biosensor for Intracellular Measurement of Malonyl-CoA","authors":"Brodie L. Ranzau,&nbsp;Tiffany D. Robinson,&nbsp;Jack M. Scully,&nbsp;Edmund D. Kapelczak,&nbsp;Teagan S. Dean,&nbsp;Tara TeSlaa and Danielle L. Schmitt*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0010310.1021/acsbiomedchemau.4c00103","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00103https://doi.org/10.1021/acsbiomedchemau.4c00103","url":null,"abstract":"<p >Malonyl-CoA is the essential building block of fatty acids and regulates cell function through protein malonylation and allosteric regulation of signaling networks. Accordingly, the production and use of malonyl-CoA is finely tuned by the cellular energy status. Most studies of malonyl-CoA dynamics rely on bulk approaches that take only a snapshot of the average metabolic state of a population of cells, missing out on heterogeneous differences in malonyl-CoA and fatty acid biosynthesis that could be occurring among a cell population. To overcome this limitation, we have developed a genetically encoded fluorescent protein-based biosensor for malonyl-CoA that can be used to capture malonyl-CoA dynamics in single cells. This biosensor, termed Malibu (<b><u>mal</u></b>onyl-CoA <b><u>i</u></b>ntracellular <b><u>b</u></b>iosensor to <b><u>u</u></b>nderstand dynamics), exhibits an excitation-ratiometric change in response to malonyl-CoA binding. We first used Malibu to monitor malonyl-CoA dynamics during inhibition of fatty acid biosynthesis using cerulenin in <i>Escherichia coli</i>, observing an increase in Malibu response in a time- and dose-dependent manner. In HeLa cells, we used Malibu to monitor the impact of fatty acid biosynthesis inhibition on malonyl-CoA dynamics in single cells, finding that two inhibitors of fatty acid biosynthesis, cerulenin and orlistat, which inhibit different steps of fatty acid biosynthesis, increase malonyl-CoA levels. Altogether, we have developed a new genetically encoded biosensor for malonyl-CoA, which can be used to study malonyl-CoA dynamics in single cells, providing an unparalleled view into fatty acid biosynthesis.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"184–193 184–193"},"PeriodicalIF":3.8,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nucleic Acid Conjugates: Unlocking Therapeutic Potential","authors":"Disha Kashyap,&nbsp; and ,&nbsp;Michael J. Booth*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0009210.1021/acsbiomedchemau.4c00092","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00092https://doi.org/10.1021/acsbiomedchemau.4c00092","url":null,"abstract":"<p >Nucleic acids have emerged as a powerful class of therapeutics. Through simple base pair complementarity, nucleic acids allow the targeting of a variety of pathologically relevant proteins and RNA molecules. However, despite the preliminary successes of nucleic acids as drugs in the clinic, limited biodistribution, inadequate delivery mechanisms, and target engagement remain key challenges in the field. A key area of research has been the chemical optimization of nucleic acid backbones to significantly enhance their “drug-like” properties. Alternatively, this review focuses on the next generation of nucleic acid chemical modifications: covalent biochemical conjugates. These conjugates are being applied to improve the delivery, functionality, and targeting. Exploiting research on heterobifunctionals, such as PROTACs, RIBOTACs, molecular glues, etc., has the potential to dramatically expand nucleic acid drug functionality and target engagement capabilities. Such next-generation chemistry-based enhancements have the potential to unlock nucleic acids as effective and versatile therapeutic agents.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"3–15 3–15"},"PeriodicalIF":3.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00092","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}