Institute of
bioorganic chemistry

Chimeric antigen receptor T cell (CAR-T cells) therapy has gained much attention in recent years owing to its well-recognized success in treating adults and children with B-cell malignancies. Very often CAR therapy can deliver considerable remission rates, and it has the potential to become part of standard-of-care treatment for acute lymphoblastic leukemia (ALL). However, current CAR-T cell therapy is still hampered by a variety of drawbacks. On-target off- tumour toxicity limits the anticancer applicability of chimaeric antigen receptor (CAR) T cells for solid tumours. One of the most troubling issues concerns the frequent induction of Cytokine Release Syndrome (CRS) resulted from overactivation of the T cells and on-target off-tumour effects. CAR therapy involves the injection of living cells with the capacity for replication. Unlike the usual side effects with pharmaceuticals that can be ameliorated by withholding drugs, or reducing dosage, CAR-T is much more difficult to regulate once it is initiated. Incorporating a safety switch for the CAR-T cells will lead to the development of safer immunotherapies. Here we show that the tumour-targeting specificity and activity of T cells with a CAR consisting of an antibody with a lysine residue that catalytically forms a reversible covalent bond with a 1,3-diketone hapten can be regulated by the concentration of a small-molecule adapter that selectively binds to the hapten and to a chosen tumour antigen via a small-molecule binder identified via a DNA-encoded library. The adapter therefore controls the formation of a covalent bond between the catalytic antibody and the hapten and the tethering of the CAR T cells to the tumour cells, and hence the cytotoxicity and specificity of the cytotoxic T cells, as we show in vitro and in mice with prostate cancer xenografts. Such small-molecule switches of T-cell cytotoxicity and specificity via an antigen-independent ‘universal’ CAR may enhance the control and safety profile of CAR-based cellular immunotherapies.

Adhesion of leukocytes is a key stage in their trafficking into sites of inflammation. This process is mediated through the interaction of integrins, selectins or CD44, while the role of galectins is not completely clear. It is known that galectins are capable of interacting with oligolactosamines of endothelial cells, and also that in vitro tandem-type galectins (Gal-4, -8 and -9) bind with high affinity to glycans of the ABH blood group system. This work shows that in a cell lines system gal-9 mediates lymphocyte adhesion to endothelial cells through binding to their H-glycan, suggesting that lymphocyte adhesion to endothelium in the circulation occurs similarly and is regulated by the level of galectin-9 expression. The work was published in the journal Biomolecules. Learn more

Proteins and other biopolymers can form in solution macrocomplexes, which at certain conditions are visible under the microscope («coacervate droplets»). The latter process is known to shape subcellular organization and for a century is considered to also impact plausible life-origin scenarios. Researchers from IBCh RAS and University of Vienna present a newly derived fractal model to describe atomistic structure of such protein condensates and using the N-terminal disordered fragment (80 residues) of the yeast transcription regulator Lge1 as a test system. The proposed theoretical model describes protein condensates across various scales in line with the general principles of colloidal system self-organization. The study combining complementary results of microsecond molecular dynamics simulations and in vitro biophysical experiments has been published in eLife. Learn more

Researchers from the Laboratory of Antibiotic Resistance and the Laboratory of Molecular Design and Synthesis at the Institute of Bioorganic Chemistry RAS, have compiled a comprehensive overview of the latest strides in phenotypic bacterial screening. The progress in novel physicochemical approaches for such screening, along with enhancements in data processing methodologies, is perspective for comprehensive frameworks to characterize microbial morphology. Notable areas of vigorous advancement encompass novel microbial profiling principles, the integration of machine learning strategies for data interpretation, and the miniaturizing of phenotyping techniques using microfluidic systems. This study was supported by the RSF grant No. 23-24-00409 and has been published in the Antibiotics journal.

Scientists from the Laboratory of Molecular Bases of Embryogenesis at the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, in collaboration with researchers from the Kharkevich Institute for Problems of Information Transmission, Russian Academy of Sciences, have pioneered a method for wide-scale identification of genes whose loss or emergence during evolution correlates with the disappearance or emergence of distinct phenotypic or physiological traits. As a proof of concept, the team pinpointed genes involved in limb regeneration among fish and amphibians, traits absent in reptiles, birds, and mammals lacking this regenerative ability. The developed approach provides an extensive range of opportunities for investigating the intricate interplay between the changes in phenotypic and physiological traits and the specific genetic transformations that occur throughout evolution. This research was supported by the Russian Science Foundation grant 23-74-30005 and published in the journal Biology Direct. Learn more