Institute of
bioorganic chemistry

Calcium-selective oncochannel TRPV6 is the major driver of cell proliferation in human cancers. That is why the development of efficient channel blockers is very important for biomedicine. At the same time, despite their pharmacological value, natural channel blockers have been previously largely neglected. Researchers from the Laboratory of Biomolecular Modeling of IBCh RAS together with colleagues from Columbia University (New York, USA) have identified structural aspects of the interaction of TRPV6 with the natural phytoestrogen genistein, which has previously shown itself in clinical studies as a blocker of cell invasion and metastasis. Using a state-of-the art biophysical approach combining cryo-EM, electrophysiology, calcium imaging, protein engineering, and molecular modeling methods, the team of scientists managed to show that genistein, binding to TRPV6, works as a pore blocker that changes the structure of the activation gate of the ion channel. The described molecular mechanism opens up new possibilities in the development of antitumor drugs. The results are published in Nature Communications. Learn more

A number of purine arabinosides containing chiral amino acid amides at the C6 position of the purine were synthesized using a transglycosylation reaction with recombinant E. coli nucleoside phosphorylases. Arsenolysis of 2-chloropurine ribosides with chiral amino acid amides at C6 was used for the enzymatic synthesis, and the reaction equilibrium shifted towards the synthesis of arabinonucleosides. The synthesized nucleosides were shown to be resistant to the action of E. coli adenosine deaminase. The antiproliferative activity of the synthesized nucleosides was studied on human acute myeloid leukemia cell line U937. Among all the compounds, the serine derivative exhibited an activity level (IC₅₀ = 16 μM) close to that of Nelarabine (IC₅₀ = 3 μM) and was evaluated as active. The work is published in the International Journal of Molecular Sciences. Learn more

Antibody-drug conjugates (ADCs) are a promising therapy for cancer. A team of researchers from the Laboratory of Molecular Design and Synthesis together with colleagues from the Laboratory of Molecular Diagnostics and the Laboratory of Lipid Chemistry of the IBCh RAS, as well as the N.N. Blokhin Russian Cancer Research Center, developed several approaches to the synthesis of conjugates of antibodies to the tumor-associated antigen PRAME with the anticancer drugs doxorubicin and MMAE. The team performed site-specific conjugation by periodate oxidation of glycans followed by bioorthogonal reactions: oxime ligation and CuAAC. Cyanine dyes were introduced into the structure of the linkers for easy determination of the stoichiometry of the conjugates. As a result, the possibility of creating antibody-drug conjugates targeting the PRAME antigen was shown for the first time. The work was published in the International Journal of Molecular Sciences.

Carriers providing active targeted delivery of anticancer drugs to tumor cells are promising for cancer chemotherapy. A team of scientists from the IBCh RAS in collaboration with collegues from other Russian Institutes have developed biodegradable polyelectrolyte microcapsules which have been modified with the DR5-B ligand. The latter is a promising recombinant analogue of the cytokine TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), which specifically binds to the DR5 death receptor overexpressed on the tumor (but not normal) cell membrane. In addition, the capsules were loaded with the anticancer drug doxorubicin (DOX) in a subtoxic concentration. The capsules were demonstrated to provide a targeted drug delivery to tumor cells, as well as a synergistic anticancer effect. The results are published in Nanomaterials. Learn more

Human InsR, IGF1R, and IRR receptor tyrosine kinases of the insulin receptor subfamily play an important role in signaling pathways for a wide range of physiological processes. Sharing high sequence and structure homology, the receptors differ dramatically in their localization, expression, and functions. A team of scientists from IBСH RAS in cooperation with colleagues from other institutions using the high-peroscopy of high resolution and computer modeling established that the conformational variability of transmembrane domains and their interaction with surrounding lipids differ significantly among representatives of the subfamily. Thus, the heterogeneous membrane environment should be taken into account in the diverse activation mechanisms of InsR, IGF1R, and IRR. This membrane-mediated control of receptor signaling offers an attractive prospect for the development of new targeted therapies for diseases associated with dysfunction of insulin subfamily receptors. The results are published in the International Journal of Molecular Sciences. Learn more