- A Uniquely Stable Trimeric Model of SARS-CoV-2 Spike Transmembrane Domain
Tools created at the Laboratory of Biomolecular Modelling IBCh RAS have been brought together into a computational framework to build a model of SARS-CoV-2 spike transmembrane domain (TMD).
- Impact of Exogenous Application of Potato Virus Y-Specific dsRNA on RNA Interference, Pattern-Triggered Immunity and Poly(ADP-ribose) Metabolism in Potato Plants
Methods for inhibition of viral infection induced by spraying plants with preparations of specific double-stranded RNAs (dsRNAs) are currently being actively developed. Researchers from the Laboratory of functional genomics and plant proteomics, the Laboratory of Molecular Diagnostics and the Laboratory of Molecular Bases of Plant Stress Resistance of the Institute of Bioorganic Chemistry RAS studied the contribution of potato plant treatment with dsRNA against potato virus Y (dsRNA-PVY) to two dsRNA-induced plant defense mechanisms: specific RNA interference (RNAi) and non-specific pattern-triggered immunity (PTI).
- SOX9 Protein in Pancreatic Cancer Regulates Multiple Cellular Networks in a Cell-Specific Manner
Pancreatic ductal adenocarcinoma is one of the most lethal cancers worldwide. Sex-determining region Y-box protein 9 (SOX9) is upregulated in the majority of pancreatic ductal adenocarcinoma cases. It is hypothesized that the increased expression of pancreatic developmental factor SOX9 is necessary for the formation and maintenance of tumor phenotypes in pancreatic cancer cells.
- Therapeutic efficacy of antibody-drug conjugates targeting GD2-positive tumors
Both ganglioside GD2-specific immunotherapy and antibody-drug conjugates (ADCs), as a class of targeted drugs, have demonstrated clinical success as solid tumor therapies in recent years, yet practically no research has been carried out on ADCs directed to ganglioside GD2. In a new study, scientists from the Department of immunology at IBCh RAS in collaboration with colleagues from other Russian institutes for the first time show that clinically relevant anti-GD2 antibody-drug conjugates manifest potent and highly selective cytotoxicity in a wide panel of cell lines with varying GD2 expression and strongly inhibit tumor growth in mouse models of GD2-positive solid cancer.
- Synthesis of New 5ʹ-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of E.coli Purine Nucleoside Phosphorylase
Scientists from the Laboratory of biosynthesis of physiologically active compounds and Laboratory of biopharmaceutical technologies (IBCH RAS) and Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences synthesized a new series of flexible 5′-norcarbocyclic aza/deaza-purine nucleoside analogs and evaluated as potential inhibitors of E. coli purine nucleoside phosphorylase.
- Positively charged black hole quencher (BHQ) derivatives as external SERS active responsive elements of biosensors
Scientists from the Group of molecular tools for living system studies (IBCh RAS), Department of chemistry of Natural Compounds (Faculty of Chemistry, MSU) and Osipyan Institute of Solid State Physics, together with the Laboratory of Molecular Design and Synthesis (IBCh RAS), have developed external SERS-active responsive elements based on positively charged black hole quencher (BHQ) derivatives.
- Lignans as Pharmacological Agents in Disorders Related to Oxidative Stress and Inflammation: Chemical Synthesis Approaches and Biological Activities
Plant lignans are active components of many herbs, which makes them the research objects for therapeutic agents development for practical use. They provide diverse naturally-occurring pharmacophores, which allows them to interact with various enzymes, receptors, ion channels and signaling molecules.
- Streptocinnamides A and B, Depsipeptides from Streptomyces sp. KMM 9044
A new structural group of antibiotics produced by a new strain Streptomyces sp. KMM 9044 was discovered as a result of teamwork of scientists from the Institute of Bioorganic Chemistry (IBCh RAS) and the Elyakov Pacific Institute of Bioorganic Chemistry (TIBOCh RAS).
- Capsule-Targeting Depolymerases Derived from Acinetobacter baumannii Prophage Regions
A team of scientists from the Laboratory of molecular bioengineering IBCh RAS together with the colleagues from other Russian Institutes bioinformatically predicted and recombinantly produced several different depolymerases encoded in the prophage regions of Acinetobacter baumannii genomes. For two depolymerases, the specificity to capsular polysaccharides (CPSs) of A. baumannii belonging to K1 and K92 capsular types (K types) was determined. These enzymes can be considered as suitable candidates for the development of new antibacterials against corresponding A. baumannii K types.
- Evolution of Phage Tail Sheath Protein
A team of scientists from the Laboratory of molecular bioengineering IBCh RAS analysed 112 contractile phage tail sheath proteins (TShP) representing different groups of bacteriophages and archaeal viruses with myoviral morphology have been modelled with the novel machine learning software, AlphaFold 2. The common core domain of all studied sheath proteins, including viral and T6SS proteins, comprised both N-terminal and C-terminal parts, whereas the other parts consisted of one or several moderately conserved domains, presumably added during phage evolution.
- Heterogeneity of the GFP fitness landscape and data-driven protein design
Understanding the relationship between genotype and phenotype, the fitness landscape, elucidates the fundamental laws of heredity (Canale et al. 2018) and may ultimately create novel methods of protein design (Alley et al. 2019). The fitness landscape is often conceptualised as a multidimensional surface (Kondrashov and Kondrashov, 2015) with one dimension representing fitness, or another phenotype, and the other dimensions each representing a genotype’s locus.
- Synthesis of 2-chloropurine ribosides with chiral amino acid amides at C6 and their evaluation as A1 adenosine receptor agonists
The team of scientists from the Department of biotechnology and the Laboratory of structural biology of ion channels IBCh RAS synthesized a series of adenosine analogs as purine ribonucleosides bearing amino acid amides at the C6 position of 2-chloropurine.
- Сytoskeleton protein Zyxin inhibits retinoic acid signaling by destabilizing maternal mRNA of nuclear receptor RXRγ
In a new study, researchers from the Laboratory of molecular bases of embryogenesis, Institute of Bioorganic Chemistry, Russian Academy of Sciences, demonstrated the versatility of the previously discovered mechanism of maternal genes mRNA destabilization caused by an interaction between the cytoskeletal protein Zyxin and the mRNA-binding factor Ybx1, showing that the same mechanism governs the retinoic acid signaling pathway during early embryonic development.
- Genetically-encoded BRET-activated photodynamic therapy for the treatment of deep-seated tumors
Being targeted to tumor cells, genetically-encoded NanoLuc-miniSOG construct generates internal light source and sensitizer pair, which makes possible PDT effect under BRET activation to treat tumors at virtually unlimited depth.
- Estimation of copy number variability from the high-throughput sequencing data
Traditionally, cytogenetic and molecular cytogenetic methods are used to detect chromosomal abnormalities. With the development of sequencing technologies, new approaches have become available to identify structural variations ranging from 50 bp. Researchers from the Laboratory of Molecular Oncology of Institute of Bioorganic Chemistry of the Russian Academy of Sciences and the Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency developed an approach for construction of CNV validation set at the exon level and evaluated the efficiency of CNV calling tools designed for whole exome sequencing data.
- 7,8-Dihydro-8-oxo-1,N6-ethenoadenine: an exclusively Hoogsteen-paired thymine mimic in DNA that induces A→T transversions in Escherichia coli
Scientists from the Group of molecular tools for living system studies and Laboratory of molecular diagnostics (IBCH) together with the colleagues from Skoltech, the Federal Research Center for Physical and Chemical Medicine, Massachusetts Institute of Technology (USA) and Instituto de Química-Física Rocasolano (Spain) has developed a DNA modification, 7,8-dihydro-8-oxo-1,N6-ethenoadenine (oxo-ϵA), a non-natural synthetic base that combines structural features of two naturally occurring DNA lesions (7,8-dihydro-8-oxoadenine and 1,N6-ethenoadenine).
- Phospholipases A2 from snake venoms inhibit HIV replication
Since the beginning of HIV epidemic, lasting more than 30 years, the main goal of scientists was to develop effective methods for the prevention and treatment of HIV infection, including the search for new compounds with high activity against HIV. Studies carried out by the staff of the Department of Molecular Neuroimmune Signaling of the Institute of Bioorganic Chemistry of the Russian Academy of Sciences and the Gamaleya National Research Center for Epidemiology and Microbiology showed that phospholipases A2 (PLA2) from snake venom have a pronounced anti-HIV effect.
- Gene therapy 2.0: AAV beyond monogenic gene correction
- Hypocrates is a genetically encoded fluorescent biosensor for (pseudo)hypohalous acids and their derivatives
The team from the Department of metabolism and redox biology together with Russian and foreign colleagues from Belgium and France, has developed a new analytical tool that allows registering (pseudo)hypohalous stress in living systems at subcellular resolution in real-time mode. The indicator was characterized in detail in vitro, and the spatial structure of a redox sensor based on a circularly permuted fluorescent protein was established for the first time. The resulting instrument was used to visualize the dynamics of active halogen species in the model of inflammation caused by the amputation of Danio rerio caudal fin. The work was published in Nature Communications journal (IF 14.919).
- Scalers: genes that regulate scale invariance of embryonic development
Embryos of many organisms are able to maintain the invariance of their structure, regardless of size – the so-called phenomenon of embryonic scaling. For example, embryos of sea urchin or frog, which have developed from individual cells isolated shortly after the beginning of egg cleavage, self-regulate their structure so that they appear as smaller copies of normal ones. Researchers at the Laboratory of Molecular Bases of Embryogenesis at the IBCH RAS have proposed a general approach to the study of the mechanisms of embryonic scaling. They heuristically postulated and then mathematically proved the existence of special genes, named scalers, the expression of which depends on the embryo size, developed a method for targeted search of such genes, and, as proof of principle, disclose the mechanism by means of which one of the found scalers, mmp3, regulates patterning of Xenopus laevis embryo in a size-dependent manner.
- FLIM-Based Intracellular and Extracellular pH Measurements Using Genetically Encoded pH Sensor
December 14, 2021
Determination of the pH value in living cells and tissues is of great importance in physiology and cell biology. Researchers from the Institute of Bioorganic Chemistry, Russian Academy of Sciences, from the Laboratory of Receptor Cell Biology, Laboratory of Molecular Theranostics and the Group of Molecular Physiology, together with colleagues from the I Prokhorov General Physics Institute and Moscow State University, a genetically encoded fluorescent sensor for measuring the pH of the extracellular medium in the slightly alkaline range has been created.
- In memory of Alexander Georgievich Petrenko
December 6, 2021
The FEBS Journal has published an obituary dedicated to our colleague, the head of the Laboratory of Receptor Cell Biology, the remarkable scientist Alexander Georgievich Petrenko, who died from COVID-19 in May 2021. The publication covers the scientific career of Alexander Petrenko, which lasted more than 4 decades. For more details on the publication, please follow the link: https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.16282
- IBCH RAS mourns passing of Richard Lerner
December 6, 2021
An outstanding scientist, director and president of the Scripps Research Institute (from 1987 to 2012), founding director of the Shanghai Institute for Advanced Immunochemical Studies, a member of the International Advisory Board of the IBCh RAS and a laureate of many international awards, Professor Richard Lerner passed away on December 2, 2021 at the age of 83. He made a huge contribution to the development of biological and medical sciences. The staff and administration of the IBCh RAS express their sincere condolences to the family, friends and colleagues of Richard Lerner.
- In vivo dynamics of acidosis and oxidative stress in the acute phase of an ischemic stroke
November 30, 2021
The team of the Department of metabolism and redox biology of Institute of Bioorganic Chemistry in collaboration with colleagues from the Federal Center of Brain Research and Neurotechnologies of the Federal Medical Biological Agency, Lomonosov Moscow State University and several other institutes have developed a technology that allows real time recording of intracellular metabolic processes in vivo. On the model of ischemic stroke in rodents, the new data were obtained on changes occurring in neurons during the development of pathology.
- Barnase*Barstar-guided two-step targeting approach for drug delivery to tumor cells in vivo
November 19, 2021
To reduce side effects in the process of oncotherapy, it seems promising to use two-step targeting delivery of active agents, or pre-targeting: at the first stage, a non-toxic targeting module (also including antibody or non-immunoglobulin scaffolds) is selectively delivered to a cell of a certain molecular profile, and at the second stage, a cytotoxic agent capable of specifically interacting with the first module is administrated into the organism.
- Antigen-specific stimulation and expansion of CAR-T cells using membrane vesicles as target cell surrogates
November 11, 2021
Development of CAR-T therapy led to immediate success in the treatment of B cell leukemia. Manufacturing of therapy-competent functional CAR-T cells needs robust protocols for ex vivo/in vitro expansion of modified T-cells. In this work, a team of scientists from the IBCh RAS in collaboration with a group of scientists from Dmitry Rogachev National Medical Research Center and colleagues from the Faculty of Biology of Moscow State University have created a new technology for the expansion of CAR T cells using artificial vesicles carrying surface tumor antigens. This approach will allow in the future to obtain CAR T-cells with improved functional properties and to minimize the level of premature "exhaustion" of the CAR T-cell population.
- Development of single-domain inhibitory antibodies targeting the ErbB3 receptor for cancer therapy
November 11, 2021
The human ErbB3 receptor is an important pharmacological target in the treatment of various types of cancer. A variety of anti-ErbB3 monoclonal antibodies are currently in development and are classic immunoglobulins. However, the search for new sources of antibodies or nanoantibodies consisting only of the heavy chain is being conducted more and more actively. Thus, in this work, a team of scientists from the Laboratory of Biocatalysis of the IBCh RAS, together with colleagues from the Laboratory of Renewable Energy Sources of the Academic University discovered a group of new single-domain llama antibodies targeting the extracellular domain of ErbB3 using the phage display method. It was found that the single-domain antibodies are not only highly affine for various receptor epitopes, but also have an inhibitory effect on the growth of tumor cells expressing ErbB3.
- Engineered Removal of PD-1 From the Surface of CD19 CAR-T Cells Results in Increased Activation and Diminished Survival
November 8, 2021
CAR-T cell therapy is the most advanced way to treat therapy resistant hematologic cancers, in particular B cell lymphomas and leukemias. T cells equipped ex vivo with chimeric receptor recognize target tumor cells and kill them. CAR-T cells that recognize CD19 marker of B cells (CD19 CAR-T) are considered the gold standard of CAR-T therapy and are approved by FDA. But in some cases, CD19 CAR-T cell therapy fails due to immune suppressive microenvironment.
- DARPin_9-29-Targeted Gold Nanorods Selectively Suppress HER2-Positive Tumor Growth in Mice
November 8, 2021
Breast cancer is one of the most common cancer among women. According to the WHO, in 2020, over 2.2 million cases of this disease were registered worldwide. High level of HER2, a tyrosine kinase receptor, is associated with a more aggressive clinical behavior and poor prognosis for breast cancer patients.
- First crystal structure of bacterial oligopeptidase B in an intermediate state: the roles of the hinge region modification and spermine
October 27, 2021
Oligopeptidase B (OpB) is a two-domain serine peptidase with trypsin-like substrate specificity. OpB belongs to the prolyl oligopeptidase (POP) family and are found only in bacteria and protozoa. It is known that OpB are pathogenesis factors of protozoan infections and protect bacterial cells from a number of antimicrobial peptides. Nevertheless, they are the least studied representatives of POP, especially bacterial OpB, for which there was a complete lack of structural information. The researches from IBC RAS together with those of NRC Kurchatov Institute and the IBOC of the National Academy of Sciences of Belarus managed to obtain crystal structures of bacterial OpB from Serratia proteomaculans (PSP) with a modified hinge region.
- Mambalgin-2 inhibits growth, migration, and invasion of metastatic melanoma cells by targeting the channels containing an asic1a subunit whose up-regulation correlates with poor survival prognosis
October 16, 2021
Melanoma is aggressive cancer characterized by acidification of extracellular environment. Scientists from the Laboratory of bioengineering of neuromodulators and neuroreceptors IBCh RAS together with colleages from NN Blokhin NMRCO showed for the first time that extracellular media acidification increases proliferation, migration, and invasion of patient-derived metastatic melanoma cells and up-regulates cell-surface expression of acid sensitive channels containing the ASIC1a, α-ENaC, and γ-ENaC subunits. No influence of media acidification on these processes was found in normal keratinocytes.
- Pseudomonas phage MD8: genetic mosaicism and challenges of taxonomic classification of lambdoid bacteriophages
October 8, 2021
Fundamental questions of the evolution of viral genomes are the most important topic of virological research. As a result of the joint work of virologists from the Laboratory of Molecular Bioengineering of the IBCh RAS and the Limnological Institute of the RAS, a group of bacteriophages of the dangerous pathogen Pseudomonas was identified, the genomes of these bacterial viruses were studied, and it was shown that their formation was greatly influenced by multiple horizontal transfers, which led to pronounced genetic mosaicism. Scientists also put forward hypotheses about the origin of the new group and proposed basic principles for the taxonomic classification of lambdoid phages.
- The secreted protein disulfide isomerase Ag1, lost by ancestors of poorly regenerating vertebrates, is required for Xenopus laevis tail regeneration
October 6, 2021
As is known, unlike cold-blooded vertebrates, warm-blooded vertebrates are not able to regenerate such complex structures as a limb or tail. Earlier, researchers from the Laboratory of Molecular Bases of Embryogenesis IBCH RAS proposed a hypothesis about the relationship between the weakening of regenerative abilities in warm-blooded animals and the loss of some genes that regulate regeneration in cold-blooded animals. In support of this hypothesis, we showed that there are indeed genes essential for the regeneration among the found genes lost by warm-blooded vertebrates, particularly the gene for the secreted disulfide isomerase Ag1. Strong activation of this gene on 1 and 2 days post-amputation of the tail in a model object, the frog Xenopus laevis tadpoles, indicated its essential role at the beginning of regeneration processes. It was shown that knockdown of ag1 reduces the ability to regenerate the amputated tail. At the same time, this ability can be restored either by overexpression of ag1 or by the addition of its recombinant protein to the tadpoles.