ACS Bio & Med Chem Au最新文献

{"title":"Exploring Possible Drug-Resistant Variants of SARS-CoV-2 Main Protease (M^pro) with Noncovalent Preclinical Candidate, Mpro61.","authors":"Jessica R Kenneson, Christina Papini, Su Tang, Kathy Huynh, Chun-Hui Zhang, William L Jorgensen, Karen S Anderson","doi":"10.1021/acsbiomedchemau.4c00109","DOIUrl":"10.1021/acsbiomedchemau.4c00109","url":null,"abstract":"<p><p>SARS-CoV-2 M^pro inhibitors, such as nirmatrelvir, have proven efficacy in clinical use. Nirmatrelvir was developed in a target-based approach against wild-type M^pro, with the anticipation that prolonged usage may cause enrichment of drug-resistant mutations and persistence of COVID infections. Although globally prevalent drug-resistant mutations have not yet been observed, individual cases have recently been reported among patients following treatment with Paxlovid-a formulation of nirmatrelvir. Mutations E166V and E166A have been detected in these drug-resistant clinical isolates, consistent with predictions from <i>in vitro</i> viral passage experiments and therefore necessitate ongoing drug development. In this study, we selected seven M^pro variants (T21I, L50F, E166V, A173V, T190I, E166V/L50F, and A173V/L50F), which have been repeatedly found in viral passage experiments. We investigated their kinetic and structural properties, as well as resistance level to M^pro inhibitors: nirmatrelvir, GC376-a similar peptidomimetic for feline COVID infections, and our in-house-developed nonpeptidomimetic inhibitor Mpro61. Mpro61 maintains potency against the single variants (except for E166V) and the A173/L50F double variant, with <i>K</i> _i values similar to those of the wild type. In contrast, while nirmatrelvir and GC376 were still effective against the A173V/L50F double variant, their <i>K</i> _i values significantly increased up to 10-fold. None of the inhibitors appeared to be potent against E166V-containing variants. Our structural analysis revealed a significant movement of Ser1 residue in all E166V-containing variants in the presence or absence of an inhibitor. The new orientation of the Ser1 suggested potential strategies for medicinal chemistry modifications of Mpro61 to enhance hydrogen-bonding interactions between these variants and Mpro61 derivatives. These studies provide critical insights into guiding the future design of additional Mpro61 derivatives that would potentially inhibit variants with the pan-drug-resistant E166V mutation.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"215-226"},"PeriodicalIF":3.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484070","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":"Exploring Possible Drug-Resistant Variants of SARS-CoV-2 Main Protease (Mpro) with Noncovalent Preclinical Candidate, Mpro61","authors":"Jessica R. Kenneson,&nbsp;Christina Papini,&nbsp;Su Tang,&nbsp;Kathy Huynh,&nbsp;Chun-Hui Zhang,&nbsp;William L. Jorgensen and Karen S. Anderson*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0010910.1021/acsbiomedchemau.4c00109","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00109https://doi.org/10.1021/acsbiomedchemau.4c00109","url":null,"abstract":"<p >SARS-CoV-2 M^pro inhibitors, such as nirmatrelvir, have proven efficacy in clinical use. Nirmatrelvir was developed in a target-based approach against wild-type M^pro, with the anticipation that prolonged usage may cause enrichment of drug-resistant mutations and persistence of COVID infections. Although globally prevalent drug-resistant mutations have not yet been observed, individual cases have recently been reported among patients following treatment with Paxlovid─a formulation of nirmatrelvir. Mutations E166V and E166A have been detected in these drug-resistant clinical isolates, consistent with predictions from <i>in vitro</i> viral passage experiments and therefore necessitate ongoing drug development. In this study, we selected seven M^pro variants (T21I, L50F, E166V, A173V, T190I, E166V/L50F, and A173V/L50F), which have been repeatedly found in viral passage experiments. We investigated their kinetic and structural properties, as well as resistance level to M^pro inhibitors: nirmatrelvir, GC376─a similar peptidomimetic for feline COVID infections, and our in-house-developed nonpeptidomimetic inhibitor Mpro61. Mpro61 maintains potency against the single variants (except for E166V) and the A173/L50F double variant, with <i>K</i>_i values similar to those of the wild type. In contrast, while nirmatrelvir and GC376 were still effective against the A173V/L50F double variant, their <i>K</i>_i values significantly increased up to 10-fold. None of the inhibitors appeared to be potent against E166V-containing variants. Our structural analysis revealed a significant movement of Ser1 residue in all E166V-containing variants in the presence or absence of an inhibitor. The new orientation of the Ser1 suggested potential strategies for medicinal chemistry modifications of Mpro61 to enhance hydrogen-bonding interactions between these variants and Mpro61 derivatives. These studies provide critical insights into guiding the future design of additional Mpro61 derivatives that would potentially inhibit variants with the pan-drug-resistant E166V mutation.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"215–226 215–226"},"PeriodicalIF":3.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435947","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":"Cation Pretreatment Enables the Saline Stability of a Near-Infrared Sensor for Dopamine","authors":"Xuewen Liu,&nbsp;Jing Chen,&nbsp;Hanxuan Wang,&nbsp;Benjamin Lambert and Ardemis A. Boghossian*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0009410.1021/acsbiomedchemau.4c00094","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00094https://doi.org/10.1021/acsbiomedchemau.4c00094","url":null,"abstract":"<p >Single-walled carbon nanotubes (SWCNTs) are wrapped with single-stranded DNA (ssDNA) to create near-infrared (NIR-II) fluorescent sensors for diverse analytes. However, the interaction between the negatively charged backbone of ssDNA and cations in biological saline alters fluorescence unpredictably. This susceptibility limits the application of these sensors in biological media. To address this limitation, this study develops a cation-pretreatment strategy that quenches the baseline fluorescence of ssDNA-SWCNTs to enable turn-on responses that are selectively triggered by analytes in saline. An initial screening of Na⁺, K⁺, Mg²⁺, Ca²⁺, and Al³⁺ pretreatments of gel-encapsulated (AT)₁₅-SWCNTs reveals that Al³⁺ pretreatment induces a stable quenching of fluorescence that is reversible only on Al³⁺ chelation or precipitation. We apply this Al³⁺ pretreatment to develop a saline-resilient, near-infrared sensor for dopamine. The Al³⁺-treated (AT)₁₅-SWCNTs show a concentration- and chirality-dependent fluorescence response over a dynamic range of 1 nM and 10 μM dopamine, achieving a 110-fold increase in the turn-on response to 10 mM dopamine in buffered saline compared with the untreated (AT)₁₅-SWCNTs. Further study of the effects of pH and different salts on the dopamine response suggests a mechanism that relies on competing trivalent cations and negative DNA phosphate interactions. These interactions lay the framework for saline-resilient optical sensors that exploit DNA as a charged-based actuator for modulating the exciton dynamics and controlling the SWCNT fluorescence.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"166–174 166–174"},"PeriodicalIF":3.8,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00094","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435942","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":"Probing the Limits of Reactant Concentration and Volume in Primitive Polyphenyllactate Synthesis and Microdroplet Assembly Processes","authors":"Mahendran Sithamparam,&nbsp;Rehana Afrin,&nbsp;Navaniswaran Tharumen,&nbsp;Ming-Jing He,&nbsp;Chen Chen,&nbsp;Ruiqin Yi,&nbsp;Po-Hsiang Wang,&nbsp;Tony Z. Jia* and Kuhan Chandru*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0008210.1021/acsbiomedchemau.4c00082","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00082https://doi.org/10.1021/acsbiomedchemau.4c00082","url":null,"abstract":"<p >Polyester microdroplets have been investigated as primitive protocell models that can exhibit relevant primitive functions such as biomolecule segregation, coalescence, and salt uptake. Such microdroplets assemble after dehydration synthesis of alpha-hydroxy acid (αHA) monomers, commonly available on early Earth, via heating at mild temperatures, followed by rehydration in aqueous media. αHAs, in particular, are also ubiquitous in biology, participating in a variety of biochemical processes such as metabolism, suggesting the possible strong link between primitive and modern αHA-based processes. Although some primitive αHA polymerization conditions have been probed previously, including monomer chirality and reaction temperature, relevant factors pertaining to early Earth’s local environmental conditions that would likely affect primitive αHA polymerization are yet to be fully investigated. Hence, probing the entire breadth of possible conditions that could promote primitive αHA polymerization is required to understand the plausibility of polyester microdroplet assembly on early Earth at the origin of life. In particular, there are numerous aqueous environments available on early Earth that could have resulted in varying volumes and concentrations of αHA accumulation, which would have affected subsequent αHA polymerization reactions. Similarly, there were likely varying levels of salt in the various aqueous prebiotic solutions, such as in the ocean, lakes, and small pools, that may have affected primitive reactions. Here, we probe the limits of the dehydration synthesis and subsequent membraneless microdroplet (MMD) assembly of phenyllactic acid (PA), a well-studied αHA relevant to both biology and prebiotic chemistry, with respect to reactant concentration and volume and salinity through mass spectrometry- and microscopy-based observations. Our study showed that polymerization and subsequent microdroplet assembly of PA appear robust even at low reactant concentrations, smaller volumes, and higher salinities than those previously tested. This indicates that PA-polyester and its microdroplets are very much viable under a wide variety of conditions, thus more likely participating in prebiotic chemistries at the origins of life.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"131–142 131–142"},"PeriodicalIF":3.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436303","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":"Probing the Limits of Reactant Concentration and Volume in Primitive Polyphenyllactate Synthesis and Microdroplet Assembly Processes.","authors":"Mahendran Sithamparam, Rehana Afrin, Navaniswaran Tharumen, Ming-Jing He, Chen Chen, Ruiqin Yi, Po-Hsiang Wang, Tony Z Jia, Kuhan Chandru","doi":"10.1021/acsbiomedchemau.4c00082","DOIUrl":"10.1021/acsbiomedchemau.4c00082","url":null,"abstract":"<p><p>Polyester microdroplets have been investigated as primitive protocell models that can exhibit relevant primitive functions such as biomolecule segregation, coalescence, and salt uptake. Such microdroplets assemble after dehydration synthesis of alpha-hydroxy acid (αHA) monomers, commonly available on early Earth, via heating at mild temperatures, followed by rehydration in aqueous media. αHAs, in particular, are also ubiquitous in biology, participating in a variety of biochemical processes such as metabolism, suggesting the possible strong link between primitive and modern αHA-based processes. Although some primitive αHA polymerization conditions have been probed previously, including monomer chirality and reaction temperature, relevant factors pertaining to early Earth's local environmental conditions that would likely affect primitive αHA polymerization are yet to be fully investigated. Hence, probing the entire breadth of possible conditions that could promote primitive αHA polymerization is required to understand the plausibility of polyester microdroplet assembly on early Earth at the origin of life. In particular, there are numerous aqueous environments available on early Earth that could have resulted in varying volumes and concentrations of αHA accumulation, which would have affected subsequent αHA polymerization reactions. Similarly, there were likely varying levels of salt in the various aqueous prebiotic solutions, such as in the ocean, lakes, and small pools, that may have affected primitive reactions. Here, we probe the limits of the dehydration synthesis and subsequent membraneless microdroplet (MMD) assembly of phenyllactic acid (PA), a well-studied αHA relevant to both biology and prebiotic chemistry, with respect to reactant concentration and volume and salinity through mass spectrometry- and microscopy-based observations. Our study showed that polymerization and subsequent microdroplet assembly of PA appear robust even at low reactant concentrations, smaller volumes, and higher salinities than those previously tested. This indicates that PA-polyester and its microdroplets are very much viable under a wide variety of conditions, thus more likely participating in prebiotic chemistries at the origins of life.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 1","pages":"131-142"},"PeriodicalIF":3.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484117","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,&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":"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":"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}