RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry

Moscow, Russia

RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry

Moscow, Russia
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Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.1.1-5 | Award Amount: 14.64M | Year: 2008

Cys-loop receptors (CLRs) form a superfamily of structurally related neurotransmitter-gated ion channels, comprising nicotinic acetylcholine, glycine, GABA-A/C and serotonin (5HT3) receptors, crucial to function of the peripheral and central nervous system. CLRs cover a wide spectrum of functions, ranging from muscle contraction to cognitive functions. CLR (mal)function is linked to various disorders, including muscular dystrophies, neurodegenerative diseases, e.g. Alzheimers and Parkinsons, and neuropsychiatric diseases, e.g. schizophrenia, epilepsy and addiction. CLRs are potentially important drug targets for treatment of disease. However, novel drug discovery strategies call for in depth understanding of ligand binding sites, the structure-function relationships of these receptors and insight into their actions in the nervous system. NeuroCypres assembles the expertise of leading European laboratories to provide a technology workflow, which enables to embark on this next step in CLR structure and function. A major target of this project is to obtain high-resolution X-ray and NMR structures for CLRs and their complexes with diverse ligands, agonists/antagonists, channel blockers and modulators, which will reveal basic mechanisms of receptor functioning from ligand binding to gating and open new avenues to rational drug design. In addition, the project aims at understanding receptor function in the context of the brain, focusing on receptor biosensors, receptor-protein interactions and transgenic models. This major challenge requires application and development of a multidisciplinary workflow of high-throughput (HT) crystallization and HT-electrophysiology technologies, X-ray analysis, NMR and computational modeling, fragment-based drug design, innovative quantitative methods of interaction-proteomics, sensitive methods for visualization of activity and localization of receptors and studies of in vitro and in vivo function in animal models of disease.

Agency: European Commission | Branch: FP7 | Program: CP-SICA | Phase: KBBE-2008-3-2-01 | Award Amount: 5.19M | Year: 2009

IRENE project aims at overcoming existing bottlenecks for a broader diffusion of biocatalysis and at accelerating the sustainable innovation of chemical industry by developing computational methods and strategies that will enable to rationally design and produce the next generation of biocatalysts for industrial applications. The consortium is funded on the combination of robust multidisciplinary expertise from EU, Russia and Uzbekistan. Due to the interaction between theoretical groups and experimentalists all computational tools used in this project will be validated by experiments. Failures and successes will be used for methods evaluation and tuning, in an iterative process that will lead to new methods but also to the definition of practical guidelines, for any specific enzyme design issue. The convergence of different expertise will face 4 main tasks: 1) fast rational design of efficient biocatalysts; 2) fast and efficient in silico screening of available enzymes/mutants to exploit catalytic potential of existing biocatalyst and providing quantitative parameters describing enzymes efficiency; 3) fast substrate-screening and rational substrate engineering; 4) understanding molecular basis of biocatalyst action and properties. IRENE will pursue these objectives by taking advantage of computational strategies used in different disciplines and integrate them in an unified concept for studying enzyme catalysis. The four main families of computational methods, Quantum Mechanics, Molecular Mechanics, Quantitative Structure Activity Relationships and Bioinformatics, will used in an integrated approach. The project will have three major design subjects: 1) introduction of new activities in specific enzyme scaffolds (reaction promiscuity); 2) improvement of catalytic activity towards specific targets (substrate promiscuity); 3) the redesign of enantioselectivity. For each subject the work will focus on different specific enzymatic activities of industrial relevance.

Tsetlin V.I.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry
Trends in Pharmacological Sciences | Year: 2015

Snake venom neurotoxins and lymphocyte antigen 6 (Ly6) proteins, most of the latter being membrane tethered by a glycosylphosphatidylinositol (GPI) anchor, have a variety of biological activities, but their three-finger (3F) folding combines them in one Ly6/neurotoxin family. Subsets of two groups, represented by α-neurotoxins and Lynx1, respectively, interact with nicotinic acetylcholine receptors (nAChR) and, hence, are of therapeutic interest for the treatment of neurodegenerative diseases, pain, and cancer. Information on the mechanisms of action and 3D structure of the binding sites, which is required for drug design, is available from the 3D structure of α-neurotoxin complexes with nAChR models. Here, I compare the structural and functional features of α-neurotoxins versus Lynx1 and its homologs to get a clearer picture of Lynx1-nAChR interactions that is necessary for fundamental science and practical applications. © 2014 Elsevier Ltd.

Utkin Y.N.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry
Toxicon | Year: 2013

Three-finger toxins (TFTs) are the main venom components of snakes from Elapidae family. Amino acid sequences of more than five hundreds TFTs are determined; these toxins form one of the largest protein families present in snake venoms. The first TFT α-bungarotoxin was isolated almost half a century ago and so far it remains a valuable tool in the study of nicotinic acetylcholine receptors. TFTs possess diverse biological activities; for example, α-neurotoxins bind specifically with high affinity to nicotinic acetylcholine receptors, while cytotoxins induce non-specific lysis in great variety of cells. These toxins are widely used as instruments in different branches of life sciences. In this review the main landmarks in TFT study are considered. These are the discovery and isolation of TFTs, determination of their structure and mode of action as well as evolution and relationship within the family. © 2012 Elsevier Ltd.

Glinka E.M.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry
Plasmid | Year: 2012

Cancer gene therapy is a promising direction for the treatment of cancer patients. A primary goal of all cancer therapies is to selectively target and kill tumour cells. Such therapies are administered via different approaches, including both viral and non-viral delivery; however, both methods have advantages and disadvantages. Transcriptional targeting enables genes encoding toxic proteins to be expressed directly in cancer cells. Numerous vectors have been created with the purpose of killing cancer cells, and some have successfully suppressed malignant tumours. Data concerning the function of vectors bearing genes that encode cytotoxic proteins under the control of different promoters, including tissue/tumour specific and constitutive promoters, is summarised here. This review focuses on vectors that bear genes encoding diphtheria toxin, Pseudomonas exotoxin A, caspases, gef, streptolysin, and melittin. Data describing the efficacy of such vectors have been summarised. Notably, there are vectors that killed cancer cell lines originating from the same type of cancer with differential efficiency. Thus, there is differential inhibition of cancer cell growth dependent on the cell line. In this review, the constructs employing genes whose expression induces cell death and the efficiency with which they suppress cancer cell growth will be summarised. © 2012 Elsevier Inc.

Sverdlov E.D.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry | Mineev K.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry
Trends in Molecular Medicine | Year: 2013

Stem cells (SCs) are thought to have great therapeutic potential, but due to continuously and stochastically arising new mutations that unpredictably change the composition of a cell population, the large-scale manufacturing of SCs with uniform properties and predictable behavior is a challenge. Quantitative evaluation of the characteristic mutation rate of a given stem cell line could be an important criterion in making the decision to use the line in medical practice. Such an evaluation could provide a new quality standard for newly derived human embryonic stem cell (hESC) lines prior to depositing them in stem cell banks. Here, we substantiate this view with simple calculations showing the effect of the mutation rate on changes in the cell population composition due to amplification. Selection of SCs with low mutation rate could reduce the risk of negative side effects during treatment. © 2013 Elsevier Ltd.

Lukyanov K.A.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry | Belousov V.V.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry
Biochimica et Biophysica Acta - General Subjects | Year: 2014

Background: Life is a constant flow of electrons via redox couples. Redox reactions determine many if not all major cellular functions. Until recently, redox processes remained hidden from direct observation in living systems due to the lack of adequate methodology. Over the last years, imaging tools including small molecule probes and genetically encoded sensors appeared, which provided, for the first time, an opportunity to visualize and, in some cases, quantify redox reactions in live cells. Genetically encoded fluorescent redox probes, such as HyPer, rxYFP and roGFPs, have been used in several models, ranging from cultured cells to transgenic animals, and now enough information has been collected to highlight advantages and pitfalls of these probes. Scope of review: In this review, we describe the main types of genetically encoded redox probes, their essential properties, advantages and disadvantages. We also provide an overview of the most important, in our opinion, results obtained using these probes. Finally, we discuss redox-dependent photoconversions of GFP and other prospective directions in redox probe development. Major conclusions: Fluorescent protein-based redox probes have important advantages such as high specificity, possibility of transgenesis and fine subcellular targeting. For proper selection of a redox sensor for a particular model, it is important to understand that HyPer and roGFP2-Orp1 are the probes for H2O 2, whereas roGFP1/2, rxYFP and roGFP2-Grx1 are the probes for GSH/GSSG redox state. Possible pH changes should be carefully controlled in experiments with HyPer and rxYFP. General significance: Genetically encoded redox probes are the only instruments allowing real-time monitoring of reactive oxygen species and thiol redox state in living cells and tissues. We believe that in the near future the palette of FP-based redox probes will be expanded to red and far-red parts of the spectrum and to other important reactive species such as NO, O2 and superoxide. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. © 2013 Elsevier B.V. All rights reserved.

Sverdlov E.D.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry
Current Gene Therapy | Year: 2011

The approaches now united under the term "gene therapy" can be divided into two broad strategies: (1) strategy using the ideology of molecular targeted therapy, but with genes in the role of agents targeted at certain molecular component(s) or pathways presumably crucial for cancer maintenance; (ii) strategy aimed at the destruction of tumors as a whole exploiting the features shared by all cancers, for example relatively fast mitotic cell division. While the first strategy is "true" gene therapy, the second one, as e.g. suicide gene therapy, is more like genetic surgery, when a surgeon just cuts off a tumor being not interested in subtle genetic mechanisms of cancer emergence and progression. This approach inherits the ideology of chemotherapy but escapes its severe toxic effects due to intracellular formation of toxic agents. Genetic surgery seems to be the most appropriate approach to combat cancer, and its simplicity is paradoxically adequate to the super-complexity of tumors. The review consists of three parts: (i) analysis of the reasons of tumor supercomplexity and fatally inevitable failure of molecular targeted therapy, (ii) general principles of the genetic surgery strategy, and (iii) examples of genetic surgery approaches with analysis of their drawbacks and the ways for their improvement. © 2011 Bentham Science Publishers.

Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: NMP-2010-4.0-1 | Award Amount: 13.81M | Year: 2011

SaveMe project will address current urgent needs for pancreatic cancer diagnosis and treatment by exploiting partners expertise and most recent research achievements for the design and development of novel modular nanosystems platform integrating new functionalized nano-core particles and active agents. The modular platform will enable the design of diverse active nanosystems per diagnostic or therapeutic application as defined by their active agent compositions. For diagnostics, superior tracers will be developed for molecular MR/PET and gamma camera imaging, enabling efficient diagnosis and guided surgery respectively. Novel functionalized nano-core systems will be conjugated with semi-confluent active shell layer. Three types of shell layers will be design: (1) novel iron oxide nanoparticles as advanced MRI contrast agents and/or (2) DOTA complexes for MRI (with Gd3\), or PET (with Ga-68), or gamma camera (with Ga-69); (3) Integrating within one tracer both iron oxide nanoparticles and DOTA-Ga-68 complexes for a sequential or simultaneous MR/PET imaging. For therapeutics, active nanosystems will be developed to deliver (1) therapeutic siRNAs or (2) anti-MP-inhibitory-scFVs. These non-classic anti-tumor drugs will be designed based on an extensive tumor degradome analysis for combining blockage of selective matrix MPs, thus preventing basic invasive and metastasis steps, with siRNA based neutralization of secondary molecular effects induced by the specific protease inhibition. Individualized degradome analysis will be developed for potential profiling of anti-MP and siRNAs based therapy per patient. To facilitate the above diagnostics and therapeutic effects, advanced tumor targeting and penetration active agents will be linked to nano-core functionalized groups, including a biocompatible PEG layer linked to tumor selective MMP substrate molecules and highly safe and potent novel somatostatin analogue peptides targeting SSTR overexpression.

Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: PEOPLE-2007-1-1-ITN | Award Amount: 4.07M | Year: 2008

The development and production of glycoarrays will provide the foreground knowledge necessary to lead to a step change in the diagnosis and treatment of diseases ranging from cancers to autoimmune diseases. Carbohydrates play a pivotal role in the molecular interactions that govern biological events at the centre of health and disease. This has become more evident as the characterisation and identification of proteins and their interactions through proteomics has advanced during the last decade. Whilst proteomics is providing a wealth of information, it does not deal with the results of post-translational modifications such as glycosylation which are frequently the driving force behind the biological activity of proteins. This lack of information is beginning to be addressed by the emerging field of glycomics, the mapping of all carbohydrate-protein interactions. The proposed training network is multidisciplinary involving carbohydrate chemistry, array technology and application. The programme offers young scientist an outstanding opportunity to be involved in the development stages of the glycoarray technology and apply this technology to important biological questions.

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