ACS Bio & Med Chem Au最新文献

{"title":"Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses","authors":"Serhat Dönmez,&nbsp;Ringaile Lapinskaite,&nbsp;Hazal Nazlican Atalay,&nbsp;Esra Tokay,&nbsp;Feray Kockar,&nbsp;Lukas Rycek*,&nbsp;Mehmet Özbil* and Tugba Boyunegmez Tumer*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0002710.1021/acsbiomedchemau.4c00027","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00027https://doi.org/10.1021/acsbiomedchemau.4c00027","url":null,"abstract":"<p >The development of multitargeted drugs represents an innovative approach to cancer treatment, aiming to enhance drug effectiveness while minimizing side effects. Herein, we sought to elucidate the inhibitory effect of selagibenzophenone B derivatives on the survival of cancer cells and dual topoisomerase I/II enzyme activity. Results demonstrated that among the compounds, <b>SelB-1</b> selectively inhibited the proliferation and migration of prostate cancer cells while exhibiting minimal effects on healthy cells. Furthermore, <b>SelB-1</b> showed a dual inhibitory effect on topoisomerases. Computational analyses mirrored the results from enzyme inhibition assays, demonstrating the compound’s strong binding affinity to the catalytic sites of the topoisomerases. To our surprise, <b>SelB-1</b> did not induce apoptosis in prostate cancer cells; instead, it induced autophagic gene expression and lipid peroxidation while reducing GSH levels, which might be associated with ferroptotic death mechanisms. To summarize, the findings suggest that <b>SelB-1</b> possesses the potential to serve as a dual topoisomerase inhibitor and can be further developed as a promising candidate for prostate cancer treatment.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 4","pages":"178–189 178–189"},"PeriodicalIF":3.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142011011","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":"Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses","authors":"Serhat Dönmez, Ringaile Lapinskaite, Hazal Nazlican Atalay, Esra Tokay, Feray Kockar, Lukas Rycek, Mehmet Özbil, Tugba Boyunegmez Tumer","doi":"10.1021/acsbiomedchemau.4c00027","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00027","url":null,"abstract":"The development of multitargeted drugs represents an innovative approach to cancer treatment, aiming to enhance drug effectiveness while minimizing side effects. Herein, we sought to elucidate the inhibitory effect of selagibenzophenone B derivatives on the survival of cancer cells and dual topoisomerase I/II enzyme activity. Results demonstrated that among the compounds, <b>SelB-1</b> selectively inhibited the proliferation and migration of prostate cancer cells while exhibiting minimal effects on healthy cells. Furthermore, <b>SelB-1</b> showed a dual inhibitory effect on topoisomerases. Computational analyses mirrored the results from enzyme inhibition assays, demonstrating the compound’s strong binding affinity to the catalytic sites of the topoisomerases. To our surprise, <b>SelB-1</b> did not induce apoptosis in prostate cancer cells; instead, it induced autophagic gene expression and lipid peroxidation while reducing GSH levels, which might be associated with ferroptotic death mechanisms. To summarize, the findings suggest that <b>SelB-1</b> possesses the potential to serve as a dual topoisomerase inhibitor and can be further developed as a promising candidate for prostate cancer treatment.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"108 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141783709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioproduction Platform to Generate Functionalized Disulfide-Constrained Peptide Analogues","authors":"Sunhee Hwang, Aaron T. Balana, Bryan Martin, Michael Clarkson, Paola Di Lello, Hao Wu, Yanjie Li, Jakob Fuhrmann, Yavuz Dagdas, Patrick Holder, Christina I. Schroeder, Stephen E. Miller, Xinxin Gao","doi":"10.1021/acsbiomedchemau.4c00026","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00026","url":null,"abstract":"Disulfide-constrained peptides (DCPs) have gained increased attention as a drug modality due to their exceptional stability and combined advantages of large biologics and small molecules. Chemical synthesis, although widely used to produce DCPs, is associated with high cost, both economically and environmentally. To reduce the dependence on solid phase peptide synthesis and the negative environmental footprint associated with it, we present a highly versatile, low-cost, and environmentally friendly bioproduction platform to generate DCPs and their conjugates as well as chemically modified or isotope-labeled DCPs. Using the DCP against the E3 ubiquitin ligase Zinc and Ring Finger 3, MK1-3.6.10, as a model peptide, we have demonstrated the use of bacterial expression, combined with Ser ligation or transglutaminase-mediated XTEN ligation, to produce multivalent MK1-3.6.10 and MK1-3.6.10 with N-terminal functional groups. We have also developed a bioproduction method for the site-specific incorporation of unnatural amino acids into recombinant DCPs by the amber codon suppression system. Lastly, we produced ¹⁵N/¹³C-labeled MK1-3.6.10 with high yield and assessed the performance of a semiautomated resonance assignment workflow that could be used to accelerate binding studies and structural characterization of DCPs. This study provides a proof of concept to generate functionalized DCPs using bioproduction, providing a potential solution to alleviate the reliance on hazardous chemicals, reduce the cost, and expedite the timeline for DCP discovery.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141614418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioproduction Platform to Generate Functionalized Disulfide-Constrained Peptide Analogues","authors":"Sunhee Hwang,&nbsp;Aaron T. Balana,&nbsp;Bryan Martin,&nbsp;Michael Clarkson,&nbsp;Paola Di Lello,&nbsp;Hao Wu,&nbsp;Yanjie Li,&nbsp;Jakob Fuhrmann,&nbsp;Yavuz Dagdas,&nbsp;Patrick Holder,&nbsp;Christina I. Schroeder,&nbsp;Stephen E. Miller* and Xinxin Gao*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0002610.1021/acsbiomedchemau.4c00026","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00026https://doi.org/10.1021/acsbiomedchemau.4c00026","url":null,"abstract":"<p >Disulfide-constrained peptides (DCPs) have gained increased attention as a drug modality due to their exceptional stability and combined advantages of large biologics and small molecules. Chemical synthesis, although widely used to produce DCPs, is associated with high cost, both economically and environmentally. To reduce the dependence on solid phase peptide synthesis and the negative environmental footprint associated with it, we present a highly versatile, low-cost, and environmentally friendly bioproduction platform to generate DCPs and their conjugates as well as chemically modified or isotope-labeled DCPs. Using the DCP against the E3 ubiquitin ligase Zinc and Ring Finger 3, MK1-3.6.10, as a model peptide, we have demonstrated the use of bacterial expression, combined with Ser ligation or transglutaminase-mediated XTEN ligation, to produce multivalent MK1-3.6.10 and MK1-3.6.10 with N-terminal functional groups. We have also developed a bioproduction method for the site-specific incorporation of unnatural amino acids into recombinant DCPs by the amber codon suppression system. Lastly, we produced ¹⁵N/¹³C-labeled MK1-3.6.10 with high yield and assessed the performance of a semiautomated resonance assignment workflow that could be used to accelerate binding studies and structural characterization of DCPs. This study provides a proof of concept to generate functionalized DCPs using bioproduction, providing a potential solution to alleviate the reliance on hazardous chemicals, reduce the cost, and expedite the timeline for DCP discovery.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 4","pages":"190–203 190–203"},"PeriodicalIF":3.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142010328","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":"Mass Spectrometry-Based Protein Footprinting Defines the Binding Pocket of Crotonylated H3K14 in the PHD1 Domain of BAF45D within the BAF Chromatin Remodeling Complex","authors":"Marissa R. Martinez,&nbsp;Janna Kiselar,&nbsp;Benlian Wang,&nbsp;Dipti Sadalge,&nbsp;Laura Zawadzke,&nbsp;Asad Taherbhoy,&nbsp;Derek Musser,&nbsp;Yunji Davenport,&nbsp;Jeremy Setser,&nbsp;Mark R. Chance* and Steve Bellon*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0000910.1021/acsbiomedchemau.4c00009","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00009https://doi.org/10.1021/acsbiomedchemau.4c00009","url":null,"abstract":"<p >The BRG-/BRM-associated factor (BAF) chromatin remodeling complex is a central actor in transcription. One mechanism by which BAF affects gene expression is via its various histone mark readers, including double plant homeodomains (DPF), located in the BAF45D subunit. DPF domains recognize lysine acetyl and acylations, including crotonylation, localized at promoters and enhancers. Despite a significant degree of conservation between DPF domains, attempts to crystallize BAF45D with a crotonylated histone 3 peptide (H3K14Cr) were unsuccessful. In addition, recent cryoEM and modeled structures failed to define the Req domain of BAF45D, which is responsible for reading lysine modifications. Thus, the precise mechanism of crotonyl group recognition and binding by BAF45D within the BAF complex remains unclear. We turned to protein footprinting mass spectrometry to map the binding interface between H3K14Cr and BAF45D. This technique is able to demarcate protein-binding interfaces by modifying surface-accessible residues and is not limited by protein size or composition. Experiments performed in the isolated DPF domain of BAF45D (BAF45D_DPF)-delineated H3K14Cr peptide binding across the PHD1 and PHD2 pockets. We observed markedly similar effects on the BAF45D subunit when assessing H3K14Cr binding in the purified full BAF complex. The ATPase motor, BRM, also displayed H3K14Cr-protected peptides in two separate domains that were subsequently evaluated in direct binding assays. These data confirm the BAF45D–crotonylamide interaction within its obligate complex and are the first to demonstrate H3K14Cr direct binding to BRM.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 4","pages":"204–213 204–213"},"PeriodicalIF":3.8,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142011107","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":"Mass Spectrometry-Based Protein Footprinting Defines the Binding Pocket of Crotonylated H3K14 in the PHD1 Domain of BAF45D within the BAF Chromatin Remodeling Complex","authors":"Marissa R. Martinez, Janna Kiselar, Benlian Wang, Dipti Sadalge, Laura Zawadzke, Asad Taherbhoy, Derek Musser, Yunji Davenport, Jeremy Setser, Mark R. Chance, Steve Bellon","doi":"10.1021/acsbiomedchemau.4c00009","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00009","url":null,"abstract":"The BRG-/BRM-associated factor (BAF) chromatin remodeling complex is a central actor in transcription. One mechanism by which BAF affects gene expression is via its various histone mark readers, including double plant homeodomains (DPF), located in the BAF45D subunit. DPF domains recognize lysine acetyl and acylations, including crotonylation, localized at promoters and enhancers. Despite a significant degree of conservation between DPF domains, attempts to crystallize BAF45D with a crotonylated histone 3 peptide (H3K14Cr) were unsuccessful. In addition, recent cryoEM and modeled structures failed to define the Req domain of BAF45D, which is responsible for reading lysine modifications. Thus, the precise mechanism of crotonyl group recognition and binding by BAF45D within the BAF complex remains unclear. We turned to protein footprinting mass spectrometry to map the binding interface between H3K14Cr and BAF45D. This technique is able to demarcate protein-binding interfaces by modifying surface-accessible residues and is not limited by protein size or composition. Experiments performed in the isolated DPF domain of BAF45D (BAF45D_DPF)-delineated H3K14Cr peptide binding across the PHD1 and PHD2 pockets. We observed markedly similar effects on the BAF45D subunit when assessing H3K14Cr binding in the purified full BAF complex. The ATPase motor, BRM, also displayed H3K14Cr-protected peptides in two separate domains that were subsequently evaluated in direct binding assays. These data confirm the BAF45D–crotonylamide interaction within its obligate complex and are the first to demonstrate H3K14Cr direct binding to BRM.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141530091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycopolymers Prepared by Alternating Ring-Opening Metathesis Polymerization Provide Access to Distinct, Multivalent Structures for the Probing of Biological Activity","authors":"Luz C. Mendez,&nbsp;Francis O. Boadi,&nbsp;Mitchell Kennedy,&nbsp;Surita R. Bhatia and Nicole S. Sampson*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0001810.1021/acsbiomedchemau.4c00018","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00018https://doi.org/10.1021/acsbiomedchemau.4c00018","url":null,"abstract":"<p >A myriad of biological processes are facilitated by ligand–receptor interactions. The low affinities of these interactions are typically enhanced by multivalent engagements to promote binding. However, each biological interaction requires a unique display and orientation of ligands. Therefore, the availability and diversity of synthetic multivalent probes are invaluable to the investigation of ligand–receptor binding interactions. Here, we report glycopolymers prepared from bicyclo[4.2.0]oct-6-ene-7-carboxamide and 4,7-dihydro-1,3-dioxepin or cyclohexene. These glycopolymers, synthesized by alternating ring-opening metathesis polymerization, display precise ligand spacing as well as the option of a hydrophobic or acetal-functionalized polymer backbone. Small-angle X-ray scattering (SAXS) data analysis revealed that these [4.2.0] glycopolymers adopted distinct conformations in solution. In aqueous media, [4.2.0]-dioxepin glycopolymers formed swollen polymer chains with rod-like, flexible structures while [4.2.0]-cyclohexene glycopolymers assumed compact, globular structures. To illustrate how these glycopolymers could aid in the exploration of ligand–receptor interactions, we incorporated the [4.2.0] glycopolymers into a biological assay to assess their potential as activators of acrosomal exocytosis (AE) in mouse sperm. The results of the biological assay confirmed that the differing structures of the [4.2.0] glycopolymers would evoke distinct biological responses; [4.2.0]-cyclohexene glycopolymers induced AE in mouse sperm while [4.2.0]-dioxepin glycopolymers did not. Herein, we provide two options for glycopolymers with low to moderate molecular weight dispersities and low cytotoxicity that can be implemented into biological assays based on the desired hydrophobicity, rigidity, and structural conformation of the polymer probe.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 4","pages":"214–225 214–225"},"PeriodicalIF":3.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142010441","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":"Glycopolymers Prepared by Alternating Ring-Opening Metathesis Polymerization Provide Access to Distinct, Multivalent Structures for the Probing of Biological Activity","authors":"Luz C. Mendez, Francis O. Boadi, Mitchell Kennedy, Surita R. Bhatia, Nicole S. Sampson","doi":"10.1021/acsbiomedchemau.4c00018","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00018","url":null,"abstract":"A myriad of biological processes are facilitated by ligand–receptor interactions. The low affinities of these interactions are typically enhanced by multivalent engagements to promote binding. However, each biological interaction requires a unique display and orientation of ligands. Therefore, the availability and diversity of synthetic multivalent probes are invaluable to the investigation of ligand–receptor binding interactions. Here, we report glycopolymers prepared from bicyclo[4.2.0]oct-6-ene-7-carboxamide and 4,7-dihydro-1,3-dioxepin or cyclohexene. These glycopolymers, synthesized by alternating ring-opening metathesis polymerization, display precise ligand spacing as well as the option of a hydrophobic or acetal-functionalized polymer backbone. Small-angle X-ray scattering (SAXS) data analysis revealed that these [4.2.0] glycopolymers adopted distinct conformations in solution. In aqueous media, [4.2.0]-dioxepin glycopolymers formed swollen polymer chains with rod-like, flexible structures while [4.2.0]-cyclohexene glycopolymers assumed compact, globular structures. To illustrate how these glycopolymers could aid in the exploration of ligand–receptor interactions, we incorporated the [4.2.0] glycopolymers into a biological assay to assess their potential as activators of acrosomal exocytosis (AE) in mouse sperm. The results of the biological assay confirmed that the differing structures of the [4.2.0] glycopolymers would evoke distinct biological responses; [4.2.0]-cyclohexene glycopolymers induced AE in mouse sperm while [4.2.0]-dioxepin glycopolymers did not. Herein, we provide two options for glycopolymers with low to moderate molecular weight dispersities and low cytotoxicity that can be implemented into biological assays based on the desired hydrophobicity, rigidity, and structural conformation of the polymer probe.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141193900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Triblock Glycopolymers with Two 10-mer Blocks of Activating Sugars Enhance the Activation of Acrosomal Exocytosis in Mouse Sperm","authors":"Luz C. Mendez,&nbsp;Mitchell Kennedy,&nbsp;Surita R. Bhatia and Nicole S. Sampson*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c00012","DOIUrl":"10.1021/acsbiomedchemau.4c00012","url":null,"abstract":"<p >Carbohydrate recognition is imperative for the induction of sperm acrosomal exocytosis (AE), an essential phenomenon in mammalian fertilization. In mouse sperm, polynorbornene 100-mers displaying fucose or mannose moieties were effective at inducing AE. In contrast, glycopolymers exhibiting glucose sugars resulted in no AE activation. To further elucidate the role of ligand density on the activation of AE in mouse sperm, a triple-stain flow cytometry assay was employed to determine the efficacy of polynorbornene block copolymers with barbell-like sequences as initiators of AE. Triblock (ABA or ABC) copolymers were synthesized by ring-opening metathesis polymerization (ROMP) with one or two activating sugars, mannose or fucose, and one nonactivating sugar, glucose. The active ligand fractions in the polymers varied from 10, 20, or 40%. Simultaneously, random copolymers comprising 20% activating ligands were prepared to confirm the importance of ligand positionality in AE activation in mouse sperm. Polynorbornene 100-mers possessing two 10-mer blocks of activating sugars were the most effective copolymers at inducing AE with levels of AE comparable to their homopolymer counterparts and more effective than their random analogues. Small-angle X-ray scattering (SAXS) was then performed to verify that there were no differences in the conformations of the glycopolymers contributing to their varying AE activity. SAXS data analysis confirmed that all of the glycopolymers assumed semiflexible cylindrical structures with similar radii and Kuhn lengths. These findings suggest that the overall ligand density of the sugar moieties in the polymer is less important than the positionality of short blocks of high-density ligands for AE activation in mouse sperm.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 3","pages":"165–177"},"PeriodicalIF":0.0,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140833130","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":"Enhanced Sequence-Specific DNA Recognition Using Oligodeoxynucleotide-Benzimidazole Conjugates","authors":"Souvik Sur,&nbsp;Suresh Pujari,&nbsp;Nihar Ranjan,&nbsp;Lidivine Azankia Temgoua,&nbsp;Sarah L. Wicks,&nbsp;Andrea Conner and Dev P. Arya*,&nbsp;","doi":"10.1021/acsbiomedchemau.3c00074","DOIUrl":"10.1021/acsbiomedchemau.3c00074","url":null,"abstract":"<p >Synthetic modification of oligodeoxynucleotides (ODNs) via conjugation to nucleic acid binding small molecules can improve hybridization and pharmacokinetic properties. In the present study, five Hoechst 33258 derived benzimidazoles were conjugated to T rich ODNs and their hybridization effectiveness was tested. Thermal denaturation studies revealed significant stabilization of complementary duplexes by ODN-benzimidazole conjugates, with the extent of stabilization being highly dependent on the length of the linker between DNA and benzimidazole. The increases in thermal stability were determined to be due to the binding of the benzimidazole moiety to the duplex. Circular dichroism and molecular modeling studies provided insights toward the influence of conjugation on duplex structure and how linker length impacts placement of the benzimidazole moiety in the minor groove. Furthermore, thermal denaturation studies with the complementary strand containing a single base mismatch or being RNA revealed that covalent conjugation of benzimidazoles to an ODN also enhances the sequence specificity. The fundamental studies reported herein provide a strategy to improve the stability and specificity properties of the ODN probes, which can be of use for targeting and diagnostics applications.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 3","pages":"154–164"},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.3c00074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140578814","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}