12 Dec 18:58
by Morimoto, M.
Immune cells in the tumor microenvironment are not only powerful regulators of immunosuppression and tumorigenesis, but also represent a dominant cell type, with tumor-associated macrophages (TAMs) comprising up to 50% of total cell mass in solid tumors. Immunotherapies such as immune checkpoint inhibitors (ICIs) derive their efficacy from this cancer-immune cell interface, however, immune-related adverse events resulting from systemic blockade remain a significant challenge. To address this need for potent, yet highly tumor-specific immunotherapies, we developed Tumor-Immune Cell Targeting Chimeras (TICTACs), antibody conjugates that are capable of selectively depleting immune checkpoint receptors such as SIRP from the surface of TAMs. These chimeric molecules consist of a synthetic glycan ligand that binds the C-type lectin CD206, a well-established TAM marker, conjugated to a non-blocking antibody that binds but does not inhibit the checkpoint receptor. By engaging CD206, which constitutively recycles between the plasma membrane and early endosomes, TICTACs facilitate robust removal of the checkpoint receptors from the surface of CD206high macrophages, while having no effect on CD206low macrophages. By decoupling antibody selectivity from its blocking function, we present a new paradigm for developing highly tumor-specific immunotherapies.
09 Dec 17:11
Does every wine carry its own chemical signature and, if so, can this be used to identify its origin? Many specialists have tried to solve this mystery, without fully succeeding. By applying artificial intelligence tools to existing data, a team from the University of Geneva (UNIGE), in collaboration with the Institute of Vine and Wine Science at the University of Bordeaux, has succeeded in identifying with 100% accuracy the chemical mark of red wines from seven major estates in the Bordeaux region.
09 Dec 17:10
by Tanja Sack, Piriththiv Dhavarasa, Daniel Szames, Siobhan O’Brien, Stephane Angers, and Shana O. Kelley
ACS Chemical Biology
DOI: 10.1021/acschembio.3c00620
04 Dec 22:02
by Alexander Carsten,
Manuel Wolters,
Martin Aepfelbacher
Current developments in super-resolution fluorescence microscopy are opening up new possibilities in molecular and cellular bacteriology. The latest applications are presented including the use of MINFLUX nanoscopy for research into secretion systems.
Abstract
Super-resolution fluorescence microscopy technologies developed over the past two decades have pushed the resolution limit for fluorescently labeled molecules into the nanometer range. These technologies have the potential to study bacterial structures, for example, macromolecular assemblies such as secretion systems, with single-molecule resolution on a millisecond time scale. Here we review recent applications of super-resolution fluorescence microscopy with a focus on bacterial secretion systems. We also describe MINFLUX fluorescence nanoscopy, a relatively new technique that promises to one day produce molecular movies of molecular machines in action.
30 Nov 19:45
by Astrid Illigmann,
Marie-Theres Vielberg,
Markus Lakemeyer,
Felix Wolf,
Taulant Dema,
Patrik Stange,
Wolfgang Kuttenlochner,
Elisa Liebhart,
Andreas Kulik,
Nicole Staudt,
Imran Malik,
Stephanie Grond,
Stephan A. Sieber,
Leonard Kaysser,
Michael Groll,
Heike Brötz-Oesterhelt
Two clpP genes next to the biosynthetic genes for the cystargolides in Kitasatospora cystarginea provided the impetus to test the natural products for anti-ClpP activity. Cystargolides emerged as covalent ClpP inhibitors and are the first β-lactones for which ClpP co-crystal structures could be solved. The molecular inhibition mechanism is presented.
Abstract
The caseinolytic protease is a highly conserved serine protease, crucial to prokaryotic and eukaryotic protein homeostasis, and a promising antibacterial and anticancer drug target. Herein, we describe the potent cystargolides as the first natural β-lactone inhibitors of the proteolytic core ClpP. Based on the discovery of two clpP genes next to the cystargolide biosynthetic gene cluster in Kitasatospora cystarginea, we explored ClpP as a potential cystargolide target. We show the inhibition of Staphylococcus aureus ClpP by cystargolide A and B by different biochemical methods in vitro. Synthesis of semisynthetic derivatives and probes with improved cell penetration allowed us to confirm ClpP as a specific target in S. aureus cells and to demonstrate the anti-virulence activity of this natural product class. Crystal structures show cystargolide A covalently bound to all 14 active sites of ClpP from S. aureus, Aquifex aeolicus, and Photorhabdus laumondii, and reveal the molecular mechanism of ClpP inhibition by β-lactones, the predominant class of ClpP inhibitors.
30 Nov 19:45
by He Yang,
Zijian Xiong,
Xingyu Heng,
Xiaomeng Niu,
Yichen Wang,
Lihua Yao,
Lele Sun,
Zhuang Liu,
Hong Chen
Click-chemistry-mediated cell membrane glycopolymer engineering is used to potentiate dendritic cell vaccines (DCV). The glycopolymer-engineering facilitates the adhesion of dendritic cells to T cells, thereby augmenting T cell activation and improving tumor immunotherapy, providing a new strategy for designing enhanced dendritic cell-based therapeutics.
Abstract
Dendritic cell vaccine (DCV) holds great potential in tumor immunotherapy owing to its potent ability in eliciting tumor-specific immune responses. Aiming at engineering enhanced DCV, we report the first effort to construct a glycopolymer-engineered DC vaccine (G-DCV) via metabolicglycoengineering and copper-free click-chemistry. Model G-DCV was prepared by firstly delivering tumor antigens, ovalbumin (OVA) into dendritic cells (DC) with fluoroalkane-grafted polyethyleneimines, followed by conjugating glycopolymers with a terminal group of dibenzocyclooctyne (DBCO) onto dendritic cells. Compared to unmodified DCV, our G-DCV could induce stronger T cell activation due to the enhanced adhesion between DCs and T cells. Notably, such G-DCV could more effectively inhibit the growth of the mouse B16-OVA (expressing OVA antigen) tumor model after adoptive transfer. Moreover, by combination with an immune checkpoint inhibitor, G-DCV showed further increased anti-tumor effects in treating different tumor models. Thus, our work provides a novel strategy to enhance the therapeutic effectiveness of DC vaccines.
27 Nov 18:39
Researchers at McMaster University have discovered unique characteristics of a mechanism used by bacteria to resist an important class of antibiotics. The new research, published in Nature Chemical Biology, shows that resistance to aminoglycoside drugs—used to treat a variety of infections—is far more complex than initially thought.
27 Nov 17:14
by Harsha Gopal Agrawal, Pravin Shankar Giri, Poonam Meena, Subha Narayan Rath, and Ashutosh Kumar Mishra
ACS Medicinal Chemistry Letters
DOI: 10.1021/acsmedchemlett.3c00446
20 Nov 17:32
by Wang, Y.-J.
Variants in the genes encoding the subunits of gamma-aminobutyric acid type A (GABAA) receptors are associated with epilepsy. To date, over 1000 clinical variants have been identified in these genes. However, the majority of these variants lack functional studies and their clinical significance is uncertain although accumulating evidence indicates that proteostasis deficiency is the major disease-causing mechanism for GABAA receptor variants. Here, we apply two state-of-the-art modeling tools, namely AlphaMissense, which uses an artificial intelligence-based approach based on AlphaFold structures, and Rhapsody, which integrates sequence evolution and known structure-based data, to predict the pathogenicity of saturating missense variants in genes that encode the major subunits of GABAA receptors in the central nervous system, including GABRA1, GABRB2, GABRB3, and GABRG2. Our results demonstrate that the predicted pathogenicity correlates well between AlphaMissense and Rhapsody although AlphaMissense tends to generate higher pathogenic probability. Furthermore, almost all annotated pathogenic variants in the ClinVar clinical database are successfully identified from the prediction, whereas uncertain variants from ClinVar partially due to the lack of experimental data are differentiated into different pathogenicity groups. The pathogenicity prediction of GABAA receptor missense variants provides a resource to the community as well as guidance for future experimental and clinical investigations.
15 Nov 17:11
by Pierre-Alexandre Lacotte
Front Microbiol. 2023 Oct 30;14:1267662. doi: 10.3389/fmicb.2023.1267662. eCollection 2023.
ABSTRACT
INTRODUCTION: The dlt operon encodes proteins responsible for the esterification of positively charged D-alanine on the wall teichoic acids and lipoteichoic acids of Gram-positive bacteria. This structural modification of the bacterial anionic surface in several species has been described to alter the physicochemical properties of the cell-wall. In addition, it has been linked to reduced sensibilities to cationic antimicrobial peptides and antibiotics.
METHODS: We studied the D-alanylation of Clostridioides difficile polysaccharides with a complete deletion of the dltDABCoperon in the 630 strain. To look for D-alanylation location, surface polysaccharides were purified and analyzed by NMR. Properties of the dltDABCmutant and the parental strains, were determined for bacterial surface's hydrophobicity, motility, adhesion, antibiotic resistance.
RESULTS: We first confirmed the role of the dltDABCoperon in D-alanylation. Then, we established the exclusive esterification of D-alanine on C. difficile lipoteichoic acid. Our data also suggest that D-alanylation modifies the cell-wall's properties, affecting the bacterial surface's hydrophobicity, motility, adhesion to biotic and abiotic surfaces,and biofilm formation. In addition, our mutant exhibitedincreased sensibilities to antibiotics linked to the membrane, especially bacitracin. A specific inhibitor DLT-1 of DltA reduces the D-alanylation rate in C. difficile but the inhibition was not sufficient to decrease the antibiotic resistance against bacitracin and vancomycin.
CONCLUSION: Our results suggest the D-alanylation of C. difficile as an interesting target to tackle C. difficile infections.
PMID:37965542 | PMC:PMC10642750 | DOI:10.3389/fmicb.2023.1267662
15 Nov 17:07
by Anooshay Khan, Cemile Elif Özçelik, Ozge Begli, Oguzhan Oguz, Mehmet Seçkin Kesici, Talip Serkan Kasırga, Salih Özçubukcu, Esra Yuca, and Urartu Ozgur Safak Seker
ACS Medicinal Chemistry Letters
DOI: 10.1021/acsmedchemlett.3c00415