ACS Bio & Med Chem Au最新文献

{"title":"Targeted Protein Degradation for Infectious Diseases: from Basic Biology to Drug Discovery","authors":"Rocío Marisol Espinoza-Chávez,&nbsp;Alessandra Salerno,&nbsp;Anastasia Liuzzi,&nbsp;Andrea Ilari,&nbsp;Andrea Milelli,&nbsp;Elisa Uliassi and Maria Laura Bolognesi*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00063","DOIUrl":"10.1021/acsbiomedchemau.2c00063","url":null,"abstract":"<p >Targeted protein degradation (TPD) is emerging as one of the most innovative strategies to tackle infectious diseases. Particularly, proteolysis-targeting chimera (PROTAC)-mediated protein degradation may offer several benefits over classical anti-infective small-molecule drugs. Because of their peculiar and catalytic mechanism of action, anti-infective PROTACs might be advantageous in terms of efficacy, toxicity, and selectivity. Importantly, PROTACs may also overcome the emergence of antimicrobial resistance. Furthermore, anti-infective PROTACs might have the potential to (i) modulate “undruggable” targets, (ii) “recycle” inhibitors from classical drug discovery approaches, and (iii) open new scenarios for combination therapies. Here, we try to address these points by discussing selected case studies of antiviral PROTACs and the first-in-class antibacterial PROTACs. Finally, we discuss how the field of PROTAC-mediated TPD might be exploited in parasitic diseases. Since no antiparasitic PROTAC has been reported yet, we also describe the parasite proteasome system. While in its infancy and with many challenges ahead, we hope that PROTAC-mediated protein degradation for infectious diseases may lead to the development of next-generation anti-infective drugs.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"3 1","pages":"32–45"},"PeriodicalIF":0.0,"publicationDate":"2022-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/25/14/bg2c00063.PMC10125329.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9711154","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":"Twenty Years of Radical SAM! The Genesis of the Superfamily","authors":"Squire J. Booker*,&nbsp; and ,&nbsp;Cody T. Lloyd,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00078","DOIUrl":"10.1021/acsbiomedchemau.2c00078","url":null,"abstract":"In 2001, Heidi Sofia and colleagues published a groundbreaking bioinformatics study of a superfamily of enzymes that use S-adenosylmethionine (SAM or AdoMet) to carry out a wide variety of reactions that proceed through mechanisms of catalysis involving organic radicals. This superfamily of enzymes is denoted by their ability to catalyze a reductive cleavage of SAM to methionine and a 5′-deoxyadenosyl 5′radical (5′-dA·) (Figure 1). These “Radical SAM” (RS) enzymes number over 700,000 unique sequences and catalyze over 100 distinct reactions, including the formation of stable protein radicals, complex rearrangements, methylation and thiolation of unactivated carbon centers, methylation of phosphinate phosphorus atoms, epimerization, carbon−carbon bond formation between sp2and sp3-hybridized carbon centers or two sp3-hybridized carbon centers, steps in the biosynthesis of complex metallocofactors, oxidative decarboxylation, hydroxylation, cyclopropanation, and dehydrogenation, among other reaction types (Figure 2). However, a large portion of the radical SAMeome is currently unannotated. Given the potential for a remaining reservoir of novel transformations, a major challenge is to develop strategies to annotate enzymes within the radical SAMeome. Moreover, the finding that many of these enzymes catalyze key reactions in bacteria that constitute the human microbiome, suggests the importance of the radical SAMeome in human health and disease. RS superfamily members all contain at least one [Fe4S4] cluster that is ligated by three cysteine residues (one for each of three Fe ions) that are most often found in a CxxxCxxC motif. This spacing of cysteines is conserved in at least 90% of all RS proteins and is one of the major determinants used to identify RS proteins bioinformatically. SAM associates to the fourth (unique) Fe ion in a bidentate fashion through its amino and carboxylate groups. When the cluster is reduced to the [Fe4S4] state, it induces the fragmentation of SAM to yield the 5′-dA·. In almost all RS reactions�except for the reaction catalyzed by TsrM and most likely similar reactions on analogous substrates�the role of the 5′-dA· is to abstract hydrogen atoms (H·) from a substrate, which typically initiates turnover. Studies from the Broderick and Hoffman laboratories have provided evidence for an intermediate that precedes 5′-dA· formation (Figure 1). This intermediate, termed omega, contains methionine bound to the unique iron ion of the [Fe4S4] cluster and a bond between the unique iron and the 5′-carbon of 5′-deoxyadenosine. This discovery highlights a similarity between this radical generating system and 5′-deoxyadenosyl 5′-cobalamin (AdoCbl), the other biological cofactor that is used to generate the 5′-dA·. The 5′-dA· had never been observed for many decades despite myriad attempts to do so by various investigators. In 1999, Magnusson, Reed, and Frey reported the use of S-3′,4′-anhydroadenosylmethionine, an allylic analogue of SAM,","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 6","pages":"538–547"},"PeriodicalIF":0.0,"publicationDate":"2022-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b5/a1/bg2c00078.PMC10114671.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9711145","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":"Platelet Response to Allergens, CXCL10, and CXCL5 in the Context of Asthma","authors":"Sarah Gruba,&nbsp;Xiaojie Wu,&nbsp;Eleni Spanolios,&nbsp;Jiayi He,&nbsp;Kang Xiong-Hang and Christy L. Haynes*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00059","DOIUrl":"10.1021/acsbiomedchemau.2c00059","url":null,"abstract":"<p >Asthma is a chronic respiratory disease initiated by a variety of factors, including allergens. During an asthma attack, the secretion of C-X-C-motif chemokine 10 (CXCL10) and chemokine ligand 5 (CCL5) causes the migration of immune cells, including platelets, into the lungs and airway. Platelets, which contain three classes of chemical messenger-filled granules, can secrete vasodilators (adenosine diphosphate and adenosine triphosphate), serotonin (a vasoconstrictor and a vasodilator, depending on the biological system), platelet-activating factor, <i>N</i>-formylmethionyl-leucyl-phenylalanine ((fMLP), a bacterial tripeptide that stimulates chemotaxis), and chemokines (CCL5, platelet factor 4 (PF4), and C-X-C-motif chemokine 12 (CXCL12)), amplifying the asthma response. The goal of this work was threefold: (1) to understand if and how the antibody immunoglobulin E (IgE), responsible for allergic reactions, affects platelet response to the common platelet activator thrombin; (2) to understand how allergen stimulation compares to thrombin stimulation; and (3) to monitor platelet response to fMLP and the chemokines CXCL10 and CCL5. Herein, high-pressure liquid chromatography with electrochemical detection and/or carbon-fiber microelectrode amperometry measured granular secretion events from platelets with and without IgE in the presence of the allergen 2,4,6-trinitrophenyl-conjugated ovalbumin (TNP-Ova), thrombin, CXCL10, or CCL5. Platelet adhesion and chemotaxis were measured using a microfluidic platform in the presence of CXCL10, CCL5, or TNP-OVA. Results indicate that IgE binding promotes δ-granule secretion in response to platelet stimulation by thrombin in bulk. Single-cell results on platelets with exogenous IgE exposure showed significant changes in the post-membrane–granule fusion behavior during chemical messenger delivery events after thrombin stimulation. In addition, TNP-Ova allergen stimulation of IgE-exposed platelets secreted serotonin to the same extent as thrombin platelet stimulation. Enhanced adhesion to endothelial cells was demonstrated by TNP-Ova stimulation. Finally, only after incubation with IgE did platelets secrete chemical messengers in response to stimulation with fMLP, CXCL10, and CCL5.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"3 1","pages":"87–96"},"PeriodicalIF":0.0,"publicationDate":"2022-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7f/5d/bg2c00059.PMC9936497.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10827243","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":"TLR4 Blockade Using Docosahexaenoic Acid Restores Vulnerability of Drug-Tolerant Tumor Cells and Prevents Breast Cancer Metastasis and Postsurgical Relapse","authors":"Mou Wang,&nbsp;Yuejing Wang,&nbsp;Renhe Liu,&nbsp;Ruilian Yu,&nbsp;Tao Gong,&nbsp;Zhirong Zhang and Yao Fu*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00061","DOIUrl":"10.1021/acsbiomedchemau.2c00061","url":null,"abstract":"<p >Nonmutational mechanisms were recently discovered leading to reversible drug tolerance. Despite the rapid elimination of a majority of tumor cells, a small subpopulation of “‘drug-tolerant”’ cells remain viable with lethal drug exposure, which may further lead to resistance or tumor relapse. Several signaling pathways are involved in the local or systemic inflammatory responses contributing to drug-induced phenotypic switch. Here, we report that Toll-like receptor 4 (TLR4)-interacting lipid docosahexaenoic acid (DHA) restores the cytotoxic effect of doxorubicin (DOX) in the lipopolysaccharide-treated breast tumor cell line 4T1, preventing the phenotypic switch to drug-tolerant cells, which significantly reduces primary tumor growth and lung metastasis in both 4T1 orthotopic and experimental metastasis models. Importantly, DHA in combination with DOX delays and inhibits tumor recurrence following surgical removal of the primary tumor. Furthermore, the coencapsulation of DHA and DOX in a nanoemulsion significantly prolongs the survival of mice in the postsurgical 4T1 tumor relapse model with significantly reduced systemic toxicity. The synergistic antitumor, antimetastasis, and antirecurrence effects of DHA + DOX combination are likely mediated by attenuating TLR4 activation, thus sensitizing tumor cells to standard chemotherapy.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"3 1","pages":"97–113"},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b2/7f/bg2c00061.PMC10125315.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9355992","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":"Antifungal Development and the Urgency of Minimizing the Impact of Fungal Diseases on Public Health","authors":"Haroldo C. de Oliveira,&nbsp;Bárbara T. Bezerra and Marcio L. Rodrigues*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00055","DOIUrl":"10.1021/acsbiomedchemau.2c00055","url":null,"abstract":"<p >Fungal infections are a major public health problem resulting from the lack of public policies addressing these diseases, toxic and/or expensive therapeutic tools, scarce diagnostic tests, and unavailable vaccines. In this Perspective, we discuss the need for novel antifungal alternatives, highlighting new initiatives based on drug repurposing and the development of novel antifungals.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"3 2","pages":"137–146"},"PeriodicalIF":0.0,"publicationDate":"2022-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e0/be/bg2c00055.PMC10125384.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9356672","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":"Substrate Specificity and Kinetics of RNA Hydrolysis by SARS-CoV-2 NSP10/14 Exonuclease","authors":"Tyler L. Dangerfield,&nbsp; and ,&nbsp;Kenneth A. Johnson*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00046","DOIUrl":"10.1021/acsbiomedchemau.2c00046","url":null,"abstract":"<p >Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes COVID-19, continues to evolve resistance to vaccines and existing antiviral therapies at an alarming rate, increasing the need for new direct-acting antiviral drugs. Despite significant advances in our fundamental understanding of the kinetics and mechanism of viral RNA replication, there are still open questions regarding how the proofreading exonuclease (NSP10/NSP14 complex) contributes to replication fidelity and resistance to nucleoside analogs. Through single turnover kinetic analysis, we show that the preferred substrate for the exonuclease is double-stranded RNA without any mismatches. Double-stranded RNA containing a 3′-terminal remdesivir was hydrolyzed at a rate similar to a correctly base-paired cognate nucleotide. Surprisingly, single-stranded RNA or duplex RNA containing a 3′-terminal mismatch was hydrolyzed at rates 125- and 45-fold slower, respectively, compared to the correctly base-paired double-stranded RNA. These results define the substrate specificity and rate of removal of remdesivir for the exonuclease and outline rigorous kinetic assays that could help in finding next-generation exonuclease inhibitors or nucleoside analogs that are able to evade excision. These results also raise important questions about the role of the polymerase/exonuclease complex in proofreading during viral replication. Addressing these questions through rigorous kinetic analysis will facilitate the search for desperately needed antiviral drugs to combat COVID-19.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 6","pages":"600–606"},"PeriodicalIF":0.0,"publicationDate":"2022-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/70/b5/bg2c00046.PMC9718090.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9427711","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":"Modeling the Effect of Cooperativity in Ternary Complex Formation and Targeted Protein Degradation Mediated by Heterobifunctional Degraders","authors":"Daniel Park,&nbsp;Jesus Izaguirre,&nbsp;Rory Coffey and Huafeng Xu*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00037","DOIUrl":"10.1021/acsbiomedchemau.2c00037","url":null,"abstract":"<p >Chemically induced proximity between certain endogenous enzymes and a protein of interest (POI) inside cells may cause post-translational modifications to the POI with biological consequences and potential therapeutic effects. Heterobifunctional (HBF) molecules that bind with one functional part to a target POI and with the other to an E3 ligase induce the formation of a target-HBF-E3 ternary complex, which can lead to ubiquitination and proteasomal degradation of the POI. Targeted protein degradation (TPD) by HBFs offers a promising approach to modulate disease-associated proteins, especially those that are intractable using other therapeutic approaches, such as enzymatic inhibition. The three-way interactions among the HBF, the target POI, and the ligase─including the protein–protein interaction between the POI and the ligase─contribute to the stability of the ternary complex, manifested as positive or negative binding cooperativity in its formation. How such cooperativity affects HBF-mediated degradation is an open question. In this work, we develop a pharmacodynamic model that describes the kinetics of the key reactions in the TPD process, and we use this model to investigate the role of cooperativity in the ternary complex formation and in the target POI degradation. Our model establishes the quantitative connection between the ternary complex stability and the degradation efficiency through the former’s effect on the rate of catalytic turnover. We also develop a statistical inference model for determining cooperativity in intracellular ternary complex formation from cellular assay data and demonstrate it by quantifying the change in cooperativity due to site-directed mutagenesis at the POI-ligase interface of the SMARCA2-ACBI1-VHL ternary complex. Our pharmacodynamic model provides a quantitative framework to dissect the complex HBF-mediated TPD process and may inform the rational design of effective HBF degraders.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"3 1","pages":"74–86"},"PeriodicalIF":0.0,"publicationDate":"2022-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/63/44/bg2c00037.PMC10125322.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9355993","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":"Unraveling the Chemistry of meso-Cl Tricarbocyanine Dyes in Conjugation Reactions for the Creation of Peptide Bonds","authors":"Rüdiger M. Exner,&nbsp;Fernando Cortezon-Tamarit,&nbsp;Haobo Ge,&nbsp;Charareh Pourzand and Sofia I. Pascu*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00053","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.2c00053","url":null,"abstract":"<p >Tricarbocyanine dyes have become popular tools in life sciences and medicine. Their near-infrared (NIR) fluorescence makes them ideal agents for imaging of thick specimens or <i>in vivo</i> imaging, <i>e.g.</i>, in fluorescence-guided surgery. Among other types of cyanine dyes, <i>meso</i>-Cl tricarbocyanine dyes have received a surge of interest, as it emerged that their high reactivity makes them inherently tumor-targeting. As such, significant research efforts have focused on conjugating these to functional moieties. However, the syntheses generally suffer from low yields. Hereby, we report on the reaction of <i>meso</i>-Cl dyes with a small selection of coupling reagents to give the corresponding keto-polymethines, potentially explaining low yields and the prevalence of monofunctionalized cyanine conjugates in the current state of the art of functional near-infrared dyes. We present the synthesis and isolation of the first keto-polymethine-based conjugate and present preliminary investigation in the prostate cancer cell lines PC3 and DU145 by confocal microscopy and discuss changes to optical properties in biological media.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"2 6","pages":"642–654"},"PeriodicalIF":0.0,"publicationDate":"2022-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.2c00053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72202262","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":"Sex-Specific Silica Nanoparticle Protein Corona Compositions Exposed to Male and Female BALB/c Mice Plasmas","authors":"Ali Akbar Ashkarran,&nbsp;Hassan Gharibi,&nbsp;Jason W. Grunberger,&nbsp;Amir Ata Saei*,&nbsp;Nitish Khurana,&nbsp;Raziye Mohammadpour,&nbsp;Hamidreza Ghandehari and Morteza Mahmoudi*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00040","DOIUrl":"10.1021/acsbiomedchemau.2c00040","url":null,"abstract":"<p >As various nanoparticles (NPs) are increasingly being used in nanomedicine products for more effective and less toxic therapy and diagnosis of diseases, there is a growing need to understand their biological fate in different sexes. Herein, we report a proof-of-concept result of sex-specific protein corona compositions on the surface of silica NPs as a function of their size and porosity upon incubation with plasma proteins of female and male BALB/c mice. Our results demonstrate substantial differences between male and female protein corona profiles on the surface of silica nanoparticles. By comparing protein abundances between male and female protein coronas of mesoporous silica nanoparticles and Stöber silica nanoparticles of ∼100, 50, and 100 nm in diameter, respectively, we detected 17, 4, and 4 distinct proteins, respectively, that were found at significantly different concentrations for these constructs. These initial findings demonstrate that animal sex can influence protein corona formation on silica NPs as a function of the physicochemical properties. A more thorough consideration of the role of plasma sex would enable nanomedicine community to design and develop safer and more efficient diagnostic and therapeutic nanomedicine products for both sexes.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"3 1","pages":"62–73"},"PeriodicalIF":0.0,"publicationDate":"2022-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9f/61/bg2c00040.PMC9936498.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10470842","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 Fluorescence-Based Assay to Probe Inhibitory Effect of Fructose Mimics on GLUT5 Transport in Breast Cancer Cells","authors":"Natasha Rana,&nbsp;Marwa A. Aziz,&nbsp;Rabah A. T. Serya,&nbsp;Deena S. Lasheen,&nbsp;Nermin Samir,&nbsp;Frank Wuest,&nbsp;Khaled A. M. Abouzid and F. G. West*,&nbsp;","doi":"10.1021/acsbiomedchemau.2c00056","DOIUrl":"10.1021/acsbiomedchemau.2c00056","url":null,"abstract":"<p >Rapid cell division and reprogramming of energy metabolism are two crucial hallmarks of cancer cells. In humans, hexose trafficking into cancer cells is mainly mediated through a family of glucose transporters (GLUTs), which are facilitative transmembrane hexose transporter proteins. In several breast cancers, fructose can functionally substitute glucose as an alternative energy supply supporting rapid proliferation. GLUT5, the principal fructose transporter, is overexpressed in human breast cancer cells, providing valuable targets for breast cancer detection as well as selective targeting of anticancer drugs using structurally modified fructose mimics. Herein, a novel fluorescence assay was designed aiming to screen a series of C-3 modified 2,5-anhydromannitol (2,5-AM) compounds as <span>d</span>-fructose analogues to explore GLUT5 binding site requirements. The synthesized probes were evaluated for their ability to inhibit the uptake of the fluorescently labeled <span>d</span>-fructose derivative 6-NBDF into EMT6 murine breast cancer cells. A few of the compounds screened demonstrated highly potent single-digit micromolar inhibition of 6-NBDF cellular uptake, which was substantially more potent than the natural substrate <span>d</span>-fructose, at a level of 100-fold or more. The results of this assay are consistent with those obtained from a previous study conducted for some selected compounds against ¹⁸F-labeled <span>d</span>-fructose-based probe 6-[¹⁸F]FDF, indicating the reproducibility of the current non-radiolabeled assay. These highly potent compounds assessed against 6-NBDF open avenues for the development of more potent probes targeting GLUT5-expressing cancerous cells.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"3 1","pages":"51–61"},"PeriodicalIF":0.0,"publicationDate":"2022-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d1/22/bg2c00056.PMC10125380.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9725803","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}