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Covalent targeting of splicing in T cells.
Cell Chem Biol
January 2025
Department of Chemical Immunology and Proteomics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address:
Article Synopsis
- The study highlights a lack of available chemical probes for proteins involved in splicing, specifically focusing on a compound called EV96 that selectively reduces a protein called ITK in T cells.
- Researchers found that the effectiveness of EV96 varies depending on the T cell state, which is influenced by different protein turnover rates and how ITK mRNA is spliced.
- The paper presents a comprehensive list of proteins tied to splicing and demonstrates that many splicing factors can be targeted using new chemical strategies, showcasing the potential for splicing-targeted therapies in immune response modulation.
Functional interplay between short antimicrobial peptides and model lipid membranes.
Bioorg Chem
December 2024
Institute of Biosciences and Bio Resources - National Research Council (IBBR-CNR), 80131 Napoli, Italy; Materias Srl, 80146 Naples, Italy. Electronic address:
Antimicrobial peptides (AMPs) are considered an attractive generation of novel antibiotics due to their advantageous properties such as a broad spectrum of antimicrobial activity against pathogens, low cytotoxicity, and drug resistance. Although they have common structural features and it has been widely demonstrated that bacterial membranes represent the main target of the peptide activity, the exact mechanism underlying the membrane perturbation by AMPs is not fully understood. Nevertheless, all the proposed modes of action implicate the preliminary interaction of AMPs with the negatively charged lipids in bacterial membranes.
View Article and Find Full Text PDFPalytoxin evokes reversible spreading depolarization in the locust CNS.
J Neurophysiol
November 2024
Department of Biology, Queen's University, Kingston, Ontario, Canada.
Spreading depolarization (SD) describes the near-complete depolarization of central nervous system (CNS) neural cells as a consequence of chemical, electrical, or metabolic perturbations. It is well established as the central mechanism underlying insect coma and various mammalian neurological dysfunctions. Despite significant progress in our understanding, the question remains: which cation channel, if any, generates SD in the CNS? Previously, we speculated that the sodium-potassium ATPase (NKA) might function as a large-conductance ion channel to initiate SD in insects, potentially mediated by a palytoxin (PLTX)-like endogenous activator.
View Article and Find Full Text PDFTime-resolved fluorescence of tryptophan characterizes membrane perturbation by cyclic lipopeptides.
Biophys J
August 2024
Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany; Center for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg, Germany; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada. Electronic address:
Viscosin is a membrane-permeabilizing, cyclic lipopeptide (CLiP) produced by Pseudomonas species. Here, we have studied four synthetic analogs (L1W, V4W, L5W, and L7W), each with one leucine (Leu; L) or valine residue exchanged for tryptophan (Trp; W) by means of time-resolved fluorescence spectroscopy of Trp. To this end, we recorded the average fluorescence lifetime, rotational correlation time and limiting anisotropy, dipolar relaxation time and limiting extent of relaxation, rate constant of acrylamide quenching, effect of HO-DO exchange, and time-resolved half-width of the spectrum in the absence and presence of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) liposomes.
View Article and Find Full Text PDFArticle Synopsis
- - The study explores the limited availability of chemical probes for splicing proteins, introducing a new probe, EV96, which selectively affects a specific immune protein (ITK) by targeting the splicing factor SF3B1 based on T cell states.
- - Mechanistic details indicate that the selective effect of EV96 is linked to variations in protein turnover and the depletion of mRNA due to alternative splicing.
- - The research also compiles a list of splicing-related proteins and demonstrates the potential of covalent chemistry to target these proteins in human T cells, highlighting the broader implications for splicing as a therapeutic target in immunology.
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