Publications
241 results found
Alzahofi N, Welz T, Robinson CL, et al., 2020, Rab27a co-ordinates actin-dependent transport by controlling organelle-associated motors and track assembly proteins, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
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- Citations: 16
Broncel M, Dominicus C, Vigetti L, et al., 2020, Profiling of myristoylation in <i>Toxoplasma</i> <i>gondii</i> reveals an <i>N</i>-myristoylated protein important for host cell penetration, ELIFE, Vol: 9, ISSN: 2050-084X
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- Citations: 12
Saunders CN, Cota E, Baum J, et al., 2020, Peptide probes for Plasmodium falciparum MyoA tail interacting protein (MTIP): exploring the druggability of the malaria parasite motor complex, ACS Chemical Biology, Vol: 15, Pages: 1313-1320, ISSN: 1554-8929
Malaria remains an endemic tropical disease, and the emergence of Plasmodium falciparum parasites resistant to current front-line medicines means that new therapeutic targets are required. The Plasmodium glideosome is a multiprotein complex thought to be essential for efficient host red blood cell invasion. At its core is a myosin motor, Myosin A (MyoA), which provides most of the force required for parasite invasion. Here, we report the design and development of improved peptide-based probes for the anchor point of MyoA, the P. falciparum MyoA tail interacting protein (PfMTIP). These probes combine low nanomolar binding affinity with significantly enhanced cell penetration and demonstrable competitive target engagement with native PfMTIP through a combination of Western blot and chemical proteomics. These results provide new insights into the potential druggability of the MTIP/MyoA interaction and a basis for the future design of inhibitors.
Maneiro M, Forte N, Shchepinova MM, et al., 2020, Antibody–PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4, ACS Chemical Biology, Vol: 15, Pages: 1306-1312, ISSN: 1554-8929
Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness of PROTACs against a wide variety of targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells of different types. Here, we describe a strategy for selective protein degradation in a specific cell type. We report the design and synthesis of a trastuzumab-PROTAC conjugate (Ab-PROTAC 3) in which E3 ligase-directed degrader activity is caged with an antibody linker which can be hydrolyzed following antibody–PROTAC internalization, releasing the active PROTAC and inducing catalytic protein degradation. We show that 3 selectively targets bromodomain-containing protein 4 (BRD4) for degradation only in HER2 positive breast cancer cell lines, while sparing HER2 negative cells. Using live cell confocal microscopy, we show internalization and lysosomal trafficking of the conjugate specifically in HER2 positive cells, leading to the release of active PROTAC in quantities sufficient to induce potent BRD4 degradation. These studies demonstrate proof-of-concept for tissue-specific BRD4 degradation, overcoming limitations of PROTAC selectivity, with significant potential for application to novel targets.
Simoes BM, Santiago-Gomez A, Chiodo C, et al., 2020, Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer, ONCOGENE, Vol: 39, Pages: 4896-4908, ISSN: 0950-9232
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- Citations: 22
Fedoryshchak R, Ocasio C, Strutton B, et al., 2020, Wheat pathogen Zymoseptoria tritici N-myristoyltransferase inhibitors: on-target antifungal activity and an unusual metabolic defense mechanism, RSC Chemical Biology, Vol: 1, Pages: 68-78, ISSN: 1747-1613
Zymoseptoria tritici is the causative agent of Septoria tritici blotch (STB), which costs billions of dollars annually to major wheat-producing countries in terms of both fungicide use and crop loss. Agricultural pathogenic fungi have acquired resistance to most commercially available fungicide classes, and the rate of discovery and development of new fungicides has stalled, demanding new approaches and insights. Here we investigate a potential mechanism of targeting an important wheat pathogen Z. tritici via inhibition of N-myristoyltransferase (NMT). We characterize Z. tritici NMT biochemically for the first time, profile the in vivo Z. tritici myristoylated proteome and identify and validate the first Z. tritici NMT inhibitors. Proteomic investigation of the downstream effects of NMT inhibition identified an unusual and novel mechanism of defense against chemical toxicity in Z. tritici through the application of comparative bioinformatics to deconvolute function from the previously largely unannotated Z. tritici proteome. Research into novel fungicidal modes-of-action is essential to satisfy an urgent unmet need for novel fungicide targets, and we anticipate that this study will serve as a useful proteomics and bioinformatics resource for researchers studying Z. tritici.
Benfield CT, MacKenzie F, Ritzefeld M, et al., 2020, Correction: Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain, Life Science Alliance, Vol: 3, ISSN: 2575-1077
Anderson DP, Benns HJ, Tate EW, et al., 2020, CRISPR-TAPE: protein-centricCRISPRguide design for targeted proteome engineering, MOLECULAR SYSTEMS BIOLOGY, Vol: 16, ISSN: 1744-4292
Shackley M, Tate EW, Brown AJH, et al., 2020, Short chain fatty acids enhance expression and activity of the umami taste receptor in enteroendocrine cells via a Gα<sub>i/o</sub> pathway
<jats:title>Abstract</jats:title><jats:p>The short chain fatty acids (SCFAs) acetate, butyrate and propionate, are produced by the fermentation of non-digestible carbohydrates by the gut microbiota. SCFAs are of interest because they regulate appetite, adiposity, metabolism, glycemic control and immunity. SCFAs act at two distinct G protein-coupled receptors (GPCRs), FFAR2 and FFAR3. These are expressed in intestinal enteroendocrine cells (EECs), where they mediate SCFA-driven anorectic gut hormone release. EECs also express other GPCRs that act as nutrient sensors, in a manner that is plastic and adaptable to the environment. SCFAs may elicit some of their health-promoting effects by altering levels of GPCRs in EECs, thus, enhancing gut sensitivity to dietary molecules. Here, we identified that exposure of the murine EEC STC-1 cell-line to a concentration of SCFAs found in the colon, specifically enhances mRNA levels of the umami taste receptors TASR1 and TASR3, without altering levels of the SCFA GPCRs, FFAR2 and FFAR3. Interestingly, treatment of EECs with propionate or butyrate, but not acetate, increased levels of umami receptor transcripts. This phenomenon was reversed by inhibiting Gα<jats:sub>i/o</jats:sub> signaling with pertussis toxin, suggesting that SCFAs act through FFAR2/3 to alter gene expression. Surprisingly, neither a FFAR3-nor a FFAR2-selective synthetic ligand could increase TASR1/TASR3 mRNA levels. We assessed the functional impact of increases in TASR1/TASR3 expression using unique pharmacological properties of the umami taste receptor; namely, the potentiation of signaling by inosine monophosphate. We found that the umami taste receptor induced inosine-1-phosphate and calcium signaling in response to L-alanine and L-monosodium glutamate, and that butyrate pretreatment significantly enhanced such signaling. Our study reveals that SCFAs may contribute to EEC adaptation and alter EEC sensitivity to bioactive n
Anderson DP, Benns HJ, Tate EW, et al., 2020, CRISPR-TAPE: protein-centric CRISPR guide design for targeted proteome engineering., Mol Syst Biol, Vol: 16
Rational molecular engineering of proteins with CRISPR-based approaches is challenged by the gene-centric nature of gRNA design tools. To address this, we have developed CRISPR-TAPE, a protein-centric gRNA design algorithm that allows users to target specific residues, or amino acid types within proteins. gRNA outputs can be customized to support maximal efficacy of homology-directed repair for engineering purposes, removing time-consuming post hoc curation, simplifying gRNA outputs and reducing CPU times.
Shchepinova MM, Hanyaloglu AC, Frost GS, et al., 2020, Chemical biology of noncanonical G protein-coupled receptor signaling: Toward advanced therapeutics, CURRENT OPINION IN CHEMICAL BIOLOGY, Vol: 56, Pages: 98-110, ISSN: 1367-5931
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- Citations: 8
de Chiara C, Homsak M, Prosser GA, et al., 2020, D-Cycloserine destruction by alanine racemase and the limit of irreversible inhibition, NATURE CHEMICAL BIOLOGY, Vol: 16, Pages: 686-+, ISSN: 1552-4450
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- Citations: 16
Kounde C, Shchepinova M, Saunders C, et al., 2020, A caged E3 ligase ligand for PROTAC-mediated protein degradation with light, Chemical Communications, Vol: 56, Pages: 5532-5535, ISSN: 1359-7345
With the intent of achieving greater spatiotemporal control of PROTAC-induced protein degradation, a light-activated degrader was designed by photocaging an essential E3 ligase binding motif in a BRD4 targeting PROTAC. Proteolysis was triggered only after a short irradiation time, the kinetics of which could be monitored by live-cell video microscopy.
Ward JA, Pinto-Fernandez A, Cornelissen L, et al., 2020, Re-Evaluating the Mechanism of Action of alpha,beta-Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 63, Pages: 3756-3762, ISSN: 0022-2623
Caengprasath N, Gonzalez-Abuin N, Shchepinova M, et al., 2020, Endosomal free fatty acid receptor 2 signaling is essential for propionate-induced anorectic gut hormone release
<jats:title>Summary</jats:title><jats:p>The ability of propionate, a short chain fatty acid produced from the fermentation of non-digestible carbohydrates in the colon, to stimulate the release of anorectic gut hormones, such as glucagon like peptide-1 (GLP-1), is an attractive approach to enhance appetite regulation, weight management and glycaemic control. Propionate induces GLP-1 release via its G protein-coupled receptor (GPCR), free fatty acid receptor 2 (FFA2); a GPCR that activates Gαi and Gαq/11 pathways. However, how pleiotropic GPCR signaling mechanisms in the gut regulates appetite is poorly understood. Here, we identify propionate-mediated G protein signaling is spatially directed within the cell via the targeting of FFA2 to very early endosomes. Furthermore, propionate activates an endosomal Gαi/p38 signaling pathway, which is essential for propionate-induced GLP-1 release in enteroendocrine cells and colonic crypts. Our study reveals that intestinal metabolites can engage membrane trafficking pathways and endosomal signaling platforms to orchestrate complex GPCR pathways within the gut.</jats:p>
Tzakoniati F, Xu H, Garcia N, et al., 2020, Development of photocrosslinking probes based on Huwentoxin-IV to map the site of interaction on Nav1.7, Cell Chemical Biology, Vol: 27, Pages: 306-313.e4, ISSN: 2451-9456
Voltage-gated sodium (Nav) channels respond to changes in the membrane potential of excitable cells through the concerted action of four voltage-sensor domains (VSDs). Subtype Nav1.7 plays an important role in the propagation of signals in pain-sensing neurons and is a target for the clinical development of novel analgesics. Certain inhibitory cystine knot (ICK) peptides produced by venomous animals potently modulate Nav1.7, however the molecular mechanisms underlying their selective binding and activity remain elusive. This study reports on the design of a library of photoprobes based on the potent spider toxin Huwentoxin-IV and the determination of the toxin binding interface on VSD2 of Nav1.7 through a photocrosslinking and tandem mass spectrometry approach. Our Huwentoxin-IV probes selectively crosslink to extracellular loop S1-2 and helix S3 of VSD2 in a chimeric channel system. Our results provide a strategy that will enable mapping of sites of interaction of other ICK peptides on Nav channels.
Rueda-Zubiaurre A, Yahiya S, Fischer O, et al., 2020, Structure-activity relationship studies of a novel class of transmission blocking antimalarials targeting male gametes., Journal of Medicinal Chemistry, Vol: 63, Pages: 2240-2262, ISSN: 0022-2623
Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention towards that goal. After carrying out a screen to discover new transmission-blocking agents, herein we report our medicinal chemistry efforts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound. We reveal key structural features for the activity of this series and identify analogues with greater potency and improved metabolic stability. We believe this study lays the groundwork for further development of this series as a transmission blocking agent.
Dian C, Inmaculada P-D, Riviere F, et al., 2020, High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation, Nature Communications, Vol: 11, Pages: 1-15, ISSN: 2041-1723
The promising drug target N-myristoyltransferase (NMT) catalyses an essential protein modification thought to occur exclusively at N-terminal glycines (Gly). Here, we present high-resolution human NMT1 structures co-crystallised with reactive cognate lipid and peptide substrates, revealing high-resolution snapshots of the entire catalytic mechanism from the initial to final reaction states. Structural comparisons, together with biochemical analysis, provide unforeseen details about how NMT1 reaches a catalytically competent conformation in which the reactive groups are brought into close proximity to enable catalysis. We demonstrate that this mechanism further supports efficient and unprecedented myristoylation of an N-terminal lysine side chain, providing evidence that NMT acts both as N-terminal-lysine and glycine myristoyltransferase.
Lucy D, Zhang L, Tate EW, 2020, A Natural Product Puts Malaria on a Low-Fat Diet, CELL CHEMICAL BIOLOGY, Vol: 27, Pages: 137-139, ISSN: 2451-9448
Fedoryshchak RO, Ocasio CA, Strutton B, et al., 2020, Wheat pathogen<i>Zymoseptoria tritici N</i>-myristoyltransferase inhibitors: on-target antifungal activity and an unusual metabolic defense mechanism
<jats:title>ABSTRACT</jats:title><jats:p><jats:italic>Zymoseptoria tritici</jats:italic>is the causative agent of<jats:italic>Septoria tritici</jats:italic>blotch (STB), which costs billions of dollars annually to major wheat-producing countries in terms of both fungicide use and crop loss. Agricultural pathogenic fungi have acquired resistance to most commercially available fungicide classes, and the rate of discovery and development of new fungicides has stalled, demanding new approaches and insights. Here we investigate a potential mechanism of targeting an important wheat pathogen<jats:italic>Z. tritici</jats:italic>via inhibition of<jats:italic>N</jats:italic>-myristoyltransferase (NMT). We characterize<jats:italic>Z. tritici</jats:italic>NMT biochemically for the first time, profile the<jats:italic>in vivo Z. tritici</jats:italic>myristoylated proteome and identify and validate the first<jats:italic>Z. tritici</jats:italic>NMT inhibitors. Proteomic investigation of the downstream effects of NMT inhibition identified an unusual and novel mechanism of defense against chemical toxicity in<jats:italic>Z. tritici</jats:italic>through the application of comparative bioinformatics to deconvolute function from the previously largely unannotated<jats:italic>Z. tritici</jats:italic>proteome. Research into novel fungicidal modes-of-action is essential to satisfy an urgent unmet need for novel fungicide targets, and we anticipate that this study will serve as a useful proteomics and bioinformatics resource for researchers studying<jats:italic>Z. tritici</jats:italic>.</jats:p>
Howard RT, Hemsley P, Petteruti P, et al., 2020, Structure-guided design and in-cell target profiling of a cell-active target engagement probe for PARP inhibitors, ACS Chemical Biology, Vol: 15, Pages: 325-333, ISSN: 1554-8929
Inhibition of the poly(ADP-ribose) polymerase (PARP) family of enzymes has become an attractive therapeutic strategy in oncology and beyond; however, chemical tools to profile PARP engagement in live cells are lacking. Herein, we report the design and application of PARPYnD, the first photoaffinity probe (AfBP) for PARP enzymes based on triple PARP1/2/6 inhibitor AZ9482, which induces multipolar spindle (MPS) formation in breast cancer cells. PARPYnD is a robust tool for profiling PARP1/2 and is used to profile clinical PARP inhibitor olaparib, identifying several novel off-target proteins. Surprisingly, while PARPYnD can enrich recombinant PARP6 spiked into cellular lysates and inhibits PARP6 in cell-free assays, it does not label PARP6 in intact cells. These data highlight an intriguing biomolecular disparity between recombinant and endogenous PARP6. PARPYnD provides a new approach to expand our knowledge of the targets of this class of compounds and the mechanisms of action of PARP inhibitors in cancer.
Benfield CT, MacKenzie F, Ritzefeld M, et al., 2020, Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain, Life Science Alliance, Vol: 3, ISSN: 2575-1077
Host interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral restriction factors. Of these, IFITM3 potently inhibits viruses that enter cells through acidic endosomes, many of which are zoonotic and emerging viruses with bats (order Chiroptera) as their natural hosts. We previously demonstrated that microbat IFITM3 is antiviral. Here, we show that bat IFITMs are characterized by strong adaptive evolution and identify a highly variable and functionally important site-codon 70-within the conserved CD225 domain of IFITMs. Mutation of this residue in microbat IFITM3 impairs restriction of representatives of four different virus families that enter cells via endosomes. This mutant shows altered subcellular localization and reduced S-palmitoylation, a phenotype copied by mutation of conserved cysteine residues in microbat IFITM3. Furthermore, we show that microbat IFITM3 is S-palmitoylated on cysteine residues C71, C72, and C105, mutation of each cysteine individually impairs virus restriction, and a triple C71A-C72A-C105A mutant loses all restriction activity, concomitant with subcellular re-localization of microbat IFITM3 to Golgi-associated sites. Thus, we propose that S-palmitoylation is critical for Chiropteran IFITM3 function and identify a key molecular determinant of IFITM3 S-palmitoylation.
Kryza T, Bock N, Lovell S, et al., 2020, The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer, Molecular Oncology, Vol: 14, Pages: 105-128, ISSN: 1574-7891
Kallikrein-related peptidase 14 (KLK14) is one of several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumour microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analysed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic and in vitro assays with the goal to identify substrates, related-signalling pathways and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neo-adjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression re-occurred in patients who developed castrate-resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14-substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14-regulated genes (Interleukin 32, midkine, Sox9), particularly an involvement of the MAPK1 and IL1RN pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumours. Additional work is necessary to determine the benefits and implications of targeting/co-targeting KLK14 in PCa as well as to
Barry R, Ruano-Gallego D, Radhakrishnan ST, et al., 2020, Faecal neutrophil elastase-antiprotease balance reflects colitis severity, Mucosal Immunology, Vol: 13, Pages: 322-333, ISSN: 1933-0219
Given the global burden of diarrheal diseases on healthcare it is surprising how little is known about the drivers of disease severity. Colitis caused by infection and inflammatory bowel disease (IBD) is characterised by neutrophil infiltration into the intestinal mucosa and yet our understanding of neutrophil responses during colitis is incomplete. Using infectious (Citrobacter rodentium) and chemical (dextran sulphate sodium; DSS) murine colitis models, as well as human IBD samples, we find that faecal neutrophil elastase (NE) activity reflects disease severity. During C. rodentium infection intestinal epithelial cells secrete the serine protease inhibitor SerpinA3N to inhibit and mitigate tissue damage caused by extracellular NE. Mice suffering from severe infection produce insufficient SerpinA3N to control excessive NE activity. This activity contributes to colitis severity as infection of these mice with a recombinant C. rodentium strain producing and secreting SerpinA3N reduces tissue damage. Thus, uncontrolled luminal NE activity is involved in severe colitis. Taken together, our findings suggest that NE activity could be a useful faecal biomarker for assessing disease severity as well as therapeutic target for both infectious and chronic inflammatory colitis.
Kennedy C, Howard R, Panyain N, et al., 2019, Activity-Based Protein Profiling, Target Discovery and Validation, Publisher: John Wiley & Sons, ISBN: 9783527345298
Additionally, the book highlights techologies that are applicable to ?difficult? targets and drugs directed at multiple targets, including chemoproteomics, activity-based protein profiling, pathway mapping, genome-wide association studies, ...
Kounde C, Shchepinova MM, Tate E, 2019, A Caged E3 Ligase Ligand for PROTAC-Mediated Protein Degradation with Light
<jats:p>A caging group has been appended to a widely used Von Hippel Lindau (VHL) E3 ligase ligand for targeted protein degradation with PROTACs. Proteolysis is triggered only after a short irradiation time allowing spatiotemporal control of the protein’s fate.</jats:p>
Conole D, Mondal M, Majmudar JD, et al., 2019, Recent Developments in Cell Permeable Deubiquitinating Enzyme Activity-Based Probes, FRONTIERS IN CHEMISTRY, Vol: 7, ISSN: 2296-2646
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- Citations: 14
Kounde C, Shchepinova MM, Tate E, 2019, A Caged E3 Ligase Ligand for PROTAC-Mediated Protein Degradation with Light
<jats:p>A caging group has been appended to a widely used Von Hippel Lindau (VHL) E3 ligase ligand for targeted protein degradation with PROTACs. Proteolysis is triggered only after a short irradiation time allowing spatiotemporal control of the protein’s fate.</jats:p>
Beard R, Gaboriau D, Gee A, et al., 2019, Chemical biology tools for probing transcytosis at the blood-brain barrier, Chemical Science, Vol: 10, Pages: 10772-10778, ISSN: 2041-6520
Absorptive- and receptor-mediated transcytosis (AMT/RMT) are widely studied strategies to deliver therapeutics across the blood–brain barrier (BBB). However, an improved understanding of the mechanism surrounding trafficking is required that could promote delivery. Accordingly, we designed a flexible platform that merged AMT and RMT motifs on a single scaffold to probe various parameters (ligand, affinity, valency, position) in a screening campaign. During this process we adapted an in vitro BBB model to reliably rank transcytosis of the vehicle library. Our results demonstrate heightened uptake and trafficking for the shuttles, with a structure–activity relationship for transcytosis emerging. Notably, due to their small size, the majority of shuttles demonstrated increased permeation compared to transferrin, with the highest performing shuttle affording a 4.9-fold increase. Consequently, we have identified novel peptide conjugates that have the capacity to act as promising brain shuttles.
McCluskey S, Haslop A, Coello C, et al., 2019, Imaging chemotherapy induced acute cardiotoxicity with 18F-labelled lipophilic cations, Journal of Nuclear Medicine, Vol: 60, Pages: 1750-1756, ISSN: 1535-5667
Many chemotherapy agents are toxic to the heart, such that increasing numbers of cancer survivors are now living with the potentially lethal cardiovascular consequences of their treatment. Earlier and more sensitive detection of chemotherapy-induced cardiotoxicity may allow improved treatment strategies and increase long-term survival. Lipophilic cation positron emission tomography (PET) tracers may be suitable for early detection of cardiotoxicity. This study aims to evaluate an 18F-labelled lipophilic phosphonium cation e.g. 18F-Mitophos, as a cardiac imaging agent, comparing it to leading PET and SPECT lipophilic cationic tracers before further assessing its potential for imaging cardiotoxicity in an acute doxorubicin (DOX) model.
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