Article
Nanoscience & Nanotechnology
Hui Wen, Qihang Wu, Chaonan Li, Tingting Sun, Zhigang Xie
Summary: Photodynamic therapy (PDT) with cationic photosensitizers has shown great potential in highly efficient antimicrobial treatment. The study successfully designed and prepared a cationic 4,4-difluoro-4-bora-3a,4adiaza-s-indacene (BODIPY) photosensitizer (BDPI-TPP) that can adhere to the surface of bacteria and exert potent antibacterial effects through both positive charges and photodynamic activity. Furthermore, the BDPI-TPP nanoparticles (BDPI-TPP NPs) can also damage preformed biofilms and promote wound healing.
ACS APPLIED NANO MATERIALS
(2022)
Article
Chemistry, Organic
M. Trapani, M. A. Castriciano, J. A. A. W. Elemans, A. Nicosia, P. Mineo, M. Cordaro
Summary: An efficient protocol for synthesizing 1-substituted uracil-6-carbaldehyde derivatives has been developed, allowing the preparation of various substituents at the N-1 position in large quantities using cost-effective precursors. These aldehyde-functionalized uracils serve as useful intermediates for preparing meso-(1-substituted 6-uracil)-derivatives of BODIPY, resulting in regioselectively functionalized dyes with a direct connection to a nucleobase. Characterization of the structures and spectroscopic/photophysical properties of the dyes was done using various analytical techniques.
Article
Chemistry, Multidisciplinary
Arturas Polita, Milda Stancikaite, Rokas Zvirblis, Karolina Maleckaite, Jelena Dodonova-Vaitkuniene, Sigitas Tumkevicius, Arun Prabha Shivabalan, Gintaras Valincius
Summary: Viscosity is a crucial characteristic of lipid membranes and plays a role in solute diffusion, lipid raft formation, and membrane fluidity. This study introduces a new membrane-targeting and water-soluble viscosity probe called BODIPY-PM, which overcomes the limitations of the commonly used probe BODIPY-C-10. The research demonstrates that BODIPY-PM is not significantly affected by solvent polarity and can accurately sense viscosity in complex biological systems, such as live cells and lipid membranes.
Article
Chemistry, Physical
Dmitry N. Pevtsov, Lyubov M. Nikolenko, Alexander V. Nevidimov, Sergey A. Tovstun, Anna V. Gadomska, Vladimir A. Kuzmin, Vladimir F. Razumov, Maria A. Trestsova, Irina A. Utepova, Oleg N. Chupakhin, Alexander V. Shchepochkin, Albina A. Valeeva, Andrey A. Rempel
Summary: A series of compounds were synthesized and investigated for their fluorescence properties in two solvents. Bright fluorescence from a locally excited state was observed for certain compounds in tetrachloroethylene solution, while intramolecular charge transfer was seen in benzene solution. The rest of the compounds exhibited locally excited fluorescence in both solvents. These results indicate an additive effect of the substituents on the activation energy of nonradiative decay.
JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY A-CHEMISTRY
(2022)
Article
Chemistry, Physical
Temmy Pegarro Vales, Sung Cho, Joomin Lee, Hoa Thi Bui, Duy Khuong Mai, Isabel Wen Badon, Heejung Lim, Wookyeong Jeong, Jong-Lae Kim, Hong-Keun Kim, Ho-Joong Kim
Summary: Functionalizing BODIPY dyes with TPP substituents enables mitochondria-targeting and photodynamic therapeutic properties, showing great potential for fluorescence-imaging-guided photodynamic therapy in cancer treatment.
JOURNAL OF MOLECULAR STRUCTURE
(2021)
Article
Chemistry, Physical
Margarida G. Santos, Juliana Araujo, Chrislaura Carmo, Leonardo Santos, Maria Filomena Botelho, Mafalda Laranjo, Abilio J. F. N. Sobral
Summary: This study aimed to find BODIPYs with characteristics compatible with human cell lines for use as imaging agents. Six BODIPY derivatives with different physicochemical characteristics were synthesized and characterized. The biocompatibility of these compounds was evaluated using various assays. The results showed that BODIPYs 3 and 6 demonstrated good uptake and low hemolytic activity.
Article
Engineering, Electrical & Electronic
Ahmad Irfan, Muhammad Imran, Renjith Thomas, Muhammad Waseem Mumtaz, Muhammad Asim Raza Basra, Sami Ullah, Mohammed A. Assiri, Abdullah G. Al-Sehemi
Summary: The optoelectronic properties of heterocyclic BODIPY fluorophores with different chalcogenide elements were investigated, with compounds containing Se atom showing significantly enhanced dielectric constant, conductivity, refractive index, and extinction coefficient values. Among the various chalcogens, the compound with Se atom was found to be the most suitable for these properties.
JOURNAL OF COMPUTATIONAL ELECTRONICS
(2021)
Article
Chemistry, Organic
Anastasiya Zobnina, Alexander Moskalensky, Aleksey Vorob'ev
Summary: The BODIPY core has become popular for designing photoremovable protecting groups, and in this paper a new molecule was synthesized and characterized for potential use as a visible light removable PPG.
Article
Chemistry, Medicinal
Ho Young Kim, Ji Youn Lee, Chia-Ju Hsieh, Aladdin Riad, Nicholas J. Izzo, Susan M. Catalano, Thomas J. A. Graham, Robert H. Mach
Summary: In this study, a panel of 46 compounds with high affinity for Sigma 2 receptors was screened. Compound (+/-)-7 and its analogue (+/-)-8 showed excellent binding affinity and subtype selectivity for Sigma 2 receptors. In vitro binding experiments indicated that the binding of these compounds to Sigma 2 receptors was dependent on TMEM97 protein expression. PET studies demonstrated that compound (+/-)-7 had higher brain uptake and specific distribution in the cortex and hypothalamus compared to compound (+/-)-8. Brain uptake or tissue binding of the radiotracer was selectively inhibited by ligands with different Sigma 2 receptor binding affinities. The results suggest that compound (+/-)-7 can be used as a PET radiotracer for imaging Sigma 2 receptor function in central nervous system disorders.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Edward S. Wragg, Patrizia Pannucci, Stephen J. Hill, Jeanette Woolard, Samantha L. Cooper
Summary: A(2A) and A(2B) adenosine receptors selectively regulate vascular tone and mean arterial pressure, while inducing tachycardia. The tachycardic response induced by A(2A) or A(2B) receptor stimulation may be mediated by an increase in sympathetic activity. Additionally, the regionally selective effects of A(2B) agonists on vascular conductance are independent of sympathetic activity.
PHARMACOLOGY RESEARCH & PERSPECTIVES
(2022)
Article
Pharmacology & Pharmacy
Sean A. Cullum, Dmitry B. Veprintsev, Stephen J. Hill
Summary: This study analysed the kinetic phases of cAMP responses to beta(2)-adrenoceptor agonists in HEK293 cells expressing low levels of endogenous beta(2)-adrenoceptor. It was found that partial agonists had reduced relative IRmax values compared to isoprenaline. Preincubation with beta(2)-adrenoceptor antagonists led to a decrease in the peak response and exacerbated the effect on IRmax values. These findings provide insights into the hemi-equilibria in low receptor reserve systems with agonist-antagonist interactions.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Pharmacology & Pharmacy
Charles S. Lay, Laura E. Kilpatrick, Peter D. Craggs, Stephen J. Hill
Summary: In this study, the signalling mechanism of IL-23 receptor complexes was explored using NanoBiT and BRET techniques. The results showed that IL-23 receptor complexes formed to the same degree with and without ligand, and signal transduction was induced upon ligand binding. These findings have important implications for drug development targeting the IL-23 receptor.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Jak Grimes, Zsombor Koszegi, Yann Lanoiselee, Tamara Miljus, Shannon L. O'Brien, Tomasz M. Stepniewski, Brian Medel-Lacruz, Mithu Baidya, Maria Makarova, Ravi Mistry, Joelle Goulding, Julia Drube, Carsten Hoffmann, Dylan M. Owen, Arun K. Shukla, Jana Selent, Stephen J. Hill, Davide Calebiro
Summary: 3-arrestin plays a key role in GPCR signaling and desensitization. This study combines single-molecule microscopy and molecular dynamics simulations to investigate the interactions between 3-arrestin, receptors, and the lipid bilayer. Surprisingly, the results show that 3-arrestin spontaneously inserts into the lipid bilayer and interacts with receptors through lateral diffusion on the plasma membrane. Furthermore, the plasma membrane stabilizes 3-arrestin after receptor interaction, allowing it to separate from the activating receptor and diffuse to clathrin-coated pits. These findings provide new insights into the mechanism of 3-arrestin function at the plasma membrane.
Review
Biochemistry & Molecular Biology
Patrizia Pannucci, Sophie R. Jefferson, Jonathan Hampshire, Samantha L. Cooper, Stephen J. Hill, Jeanette Woolard
Summary: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection responsible for COVID-19 commonly leads to dyspnea and fatigue, primarily affecting the lungs. However, it can also result in dysfunction of extra-pulmonary organs, particularly the cardiovascular system. Cardiac complications such as hypertension, thromboembolism, arrhythmia, and heart failure have been observed in COVID-19 patients, with myocardial injury and myocarditis being the most frequent. Understanding the mechanisms of COVID-19-induced myocarditis, including changes in ACE2 expression and immune responses, is crucial.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Sebastian Dekkers, Birgit Caspar, Joelle Goulding, Nicholas D. Kindon, Laura E. Kilpatrick, Leigh A. Stoddart, Stephen J. Briddon, Barrie Kellam, Stephen J. Hill, Michael J. Stocks
Summary: In this study, fluorescent probes based on previously reported small-molecule antagonists were designed and synthesized using classic medicinal chemistry approaches to investigate the pharmacology and cellular distribution of the CXCR4 receptor. Three distinct chemical classes of fluorescent probes were developed and shown to specifically bind to the CXCR4 receptor in a fluorescence-based NanoBRET binding assay (pKD ranging 6.6-7.1). These probes were also used in competition binding experiments and confocal microscopy to further explore the pharmacology and cellular distribution of CXCR4.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Luke A. Adams, Lorna E. Wilkinson-White, Menachem J. Gunzburg, Stephen J. Headey, Biswaranjan Mohanty, Martin J. Scanlon, Ben Capuano, Joel P. Mackay, Bradley C. Doak
Summary: A systematic workflow, called Rapid Elaboration of Fragments into Leads (REFiL), allows for the rapid improvement of binding affinity and evolution of low-affinity fragment hits into higher-affinity leads without the need for structural information.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Charles S. Lay, Albert Isidro-Llobet, Laura E. Kilpatrick, Peter D. Craggs, Stephen J. Hill
Summary: Using a fluorescent version of IL-23, this study characterized antagonists of the full-length receptor expressed by living cells and developed a cyclic peptide fluorescent probe specific to the IL23p19:IL23R interface to further study receptor antagonists. The study also demonstrated that the immunocompromising C115Y IL23R mutation disrupts the binding epitope for IL23p19.
NATURE COMMUNICATIONS
(2023)
Article
Pharmacology & Pharmacy
Marieke Van Daele, Laura E. Kilpatrick, Jeanette Woolard, Stephen J. Hill
Summary: Vascular endothelial growth factor (VEGF) is crucial for angiogenesis and vascular endothelial cell functions. The study developed a ligand-binding assay to monitor the binding affinity and kinetics of different tyrosine kinase inhibitors (TKIs) to VEGF receptor 2 (VEGFR2). The results showed that compounds inhibiting the binding of a fluorescent analogue of sunitinib (sunitinib-red) also attenuated VEGFR2-mediated signaling, suggesting potential cardiovascular liabilities.
BIOCHEMICAL PHARMACOLOGY
(2023)
Review
Pharmacology & Pharmacy
Stephen J. Hill, Laura E. Kilpatrick
Summary: Equilibrium binding assays are commonly used in drug discovery to evaluate drug-receptor interactions, but there is increasing interest in studying the kinetics of these interactions. Drugs can induce conformational changes in the orthosteric binding site, leading to alterations in the association and dissociation rates of orthosteric ligands. This review provides an overview of how fluorescent ligand technologies are used to study ligand-receptor kinetics in living cells and the insights they offer into conformational changes induced by drugs targeting cell surface receptors.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Chemistry, Medicinal
Bianca Maria Casella, James P. P. Farmer, Desislava N. N. Nesheva, Huw E. L. Williams, Steven J. J. Charlton, Nicholas D. D. Holliday, Charles A. A. Laughton, Shailesh N. N. Mistry
Summary: Inhibition of CXCR2 is a potential strategy for the treatment of pulmonary diseases and cancers. This study reports the design and synthesis of fluorescent NAMs that selectively bind to CXCR2, enabling the measurement and evaluation of their pharmacological properties. These NAMs can be used as alternative compounds for targeting these receptors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Lydia Ogrodzinski, Simon Platt, Joelle Goulding, Cameron Alexander, Tracy D. Farr, Jeanette Woolard, Stephen J. Hill, Laura E. Kilpatrick
Summary: E-selectin is a protein expressed on endothelial cells in response to inflammatory cytokines, and it plays a role in leukocyte rolling and extravasation. This study used CRISPR-Cas9 genome editing and NanoLuc Binary Technology (NanoBiT) to tag endogenous E-selectin in human umbilical vein endothelial cells (HUVECs) and monitor its expression in real time. The combination of NanoBiT and CRISPR-Cas9 gene editing provides a powerful tool for monitoring dynamic changes in E-selectin expression on cell surfaces, which can contribute to the discovery of drugs targeting this important inflammatory protein.
Article
Hematology
Foteini-Nafsika Damaskinaki, Natalie J. Jooss, Eleyna M. Martin, Joanne C. Clark, Mark R. Thomas, Natalie S. Poulter, Jonas Emsley, Barrie Kellam, Steve P. Watson, Alexandre Slater
Summary: This study investigates the binding sites of three high-affinity nanobodies, Nb2, Nb21, and Nb35, on the platelet-signaling receptor GPVI. The researchers found that all three nanobodies can bind to the D1 domain of GPVI and inhibit collagen-induced GPVI signaling. They also identified common target residues, Arg46, Tyr47, and Ala57, on GPVI for these nanobodies. Additionally, the study negates the idea that GPVI dimerization induces a conformational change required for ligand binding.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Meeting Abstract
Pharmacology & Pharmacy
James Farmer, Nicholas Holliday, Shailesh Mistry, Charles Laughton
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
