Institute of
bioorganic chemistry

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

Scientists from IBCH RAS, together with colleagues from the Federal Research Center for Physical and Chemical Medicine and other Russian institutes, have developed a platform for fluorescent imaging of small non-coding RNAs (sncRNAs) in living cells. The system consists of a fluorogenic cyanine dye and a genetically encoded Mango II aptamer-based label, which is attached to the sncRNA of interest and causes an increase in dye fluorescence upon complex formation. An approach to optimizing the spectral properties of dyes was proposed and a minimal genetically encoded label (52 nt) for sncRNA visualization was developed. The applicability of the system for intracellular imaging and tracking of sncRNA was verified using an intracellular internalization of Mycobacterium smegmatis by a host macrophage. The work was published in Nucleic Acids Research.

A group of scientists from the Laboratory of Molecular Biophysics and the Laboratory of Carbohydrates of the IBCH RAS, the A.V. Shubnikov Institute of Crystallography, and the European Molecular Biology Laboratory (Hamburg) developed a new approach to study the structure of nanoparticles by combining SAXS and molecular dynamics. In their paper, published in Colloids and Surfaces B: Biointerfaces, they characterized the surface structure of core-shell nanoparticles formed by biotin-CMG2-DOPE amphiphil using SAXS contrast variation and low-resolution Ab initio structure restoration. This approach demonstrates heterogeneity of the nanoparticles surface through a non-uniform distribution of the polar CMG2 spacer around the nonpolar core, localized in the form of patches. The data were verified by comparing with all-atom nanoparticle structure obtained from molecular dynamics simulation, indicating the efficacy of SAXS contrast variation to assess surface structure heterogeneity of multi-phase nanoparticles. Learn more