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Biochemistry and Bioorganic Chemistry

Biochemistry and Bioorganic Chemistry

CHYBI CHARAKTERISTIKA PROGRAMU

The aim of this programme is to prepare highly qualified professionals capable of independent scientific work, who will be involved in the implementation of new visions and methods in practice or will continue their scientific work at universities and scientific institutes and thus contribute to clarifying the functional principles of living organisms. The programme Biochemistry and Bioorganic Chemistry was created by merging two fields of chemistry. In this way, it will educate specialists preferentially oriented either to biochemistry or to bioorganic chemistry. The common denominator of both fields is to identify the chemical nature of important processes in living organisms, to study the relationship between the structure and biological activity of biopolymers, as well as natural organic compounds or their synthetic analogues.

Careers

Graduates of this programme are able to apply their knowledge in various fields such as biochemistry, cell biology and molecular genetics, microbiology, organic chemistry and chemistry of natural compounds (in relation to the dissertation topic). Based on the acquired knowledge, the student is able to plan the research project independently, critically assess the risks of the proposed procedures and apply innovative research methods. Another acquired competency of the graduate is the pedagogical and managerial experience due to involvment in teaching of bachelor and master programs, primarily in the role of assistants in laboratory courses and consultations of bachelor and master theses. Theoretical, experimental, pedagogical and managerial experience predispose the graduates to creative scientific and research activities, which is increasingly sought at various institutions of the institutes of the Academy of Sciences of the Czech Republic, universities, medical facilities, pharmaceutical companies and state and private research laboratories in the Czech Republic and abroad, dealing with problems in the field of biochemistry and bioorganic chemistry.

Programme Details

Language of instruction English
Standard length of study 4 years
Form of study Full time + Combined
Guarantor of study programme doc. Ing. Petra Lipovová, Ph.D.
Programme Code AD304
Place of study Prague
Capacity 20 students
Number of available PhD theses 21

List of available PhD theses

3D superresolution microscopy for accessing mitochondrial ultramorphology

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: RNDr. Petr Ježek, CSc.

Annotation

3D nanoscopy has not yet assessed mitochondrial cristae morphology, nor the internal structure of mitochondrial DNA (mtDNA) & protein complexes, termed nucleoids. Hence, we’ll survey 3D-redistribution of cristae and their shaping proteins or nucleois employing our prototype Vutara 3D superresolution microscope for stochastic techniques such a PALM and dSTORM. We will conduct studies under physiological situations vs. pathology (type-2 diabetes, cancer) using dSTORM with nanobodies or FRET excited PALM/dSTORM. Thus nm changes will be reflected by novel 3D nanoscopy methods. Also mtDNA nucleoids will be studied at increased and diminished mitochondrial biogenesis, while applying own mitoFISH nanoscopy for D-loop counting. Artificial manipulations of nucleoid size and mtDNA content will be studied as well as nucleoid division. Results will be translated into specific protocols for 3D nanoscopy, specifically developing novel relevant 3D image analyses based upon the Ripley’s K-function and Delaunay algorithm. Molecular cell biology will thus be combined with up-to-date 3D nanoscopy. Note, the molecular biology techniques will be conducted and be ready for the applicants by the coworkers of the Department No.75.

Approaches to the Total Synthesis of Fumiquinazoline-Based Pyrazinoquinazoline Alkaloids and Analogs

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Dr. habil. Ullrich Jahn

Annotation

In this project, short and bioinspired synthetic approaches to complex fumiquinazoline-based pyrazinoquinazoline alkaloids will be developed. The total syntheses will be modular and aimed at investigating their biological profiles in collaboration. Small focussed libraries of analogs are envisaged to complement the total syntheses of the natural products.

Approaches to the Total Synthesis of Glyantrypine-Based Pyrazinoquinazoline Alkaloids and Analogs

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Dr. habil. Ullrich Jahn

Annotation

In this project, short and bioinspired synthetic approaches to complex glyantrypine-based pyrazinoquinazoline alkaloids will be developed. The total syntheses will be modular and aimed at investigating their unknown biological profiles in collaboration. Small focussed libraries of analogs are envisaged to complement the total syntheses of the natural products.

Cathepsin proteases in biomedicine

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: RNDr. Michael Mareš, CSc.

Annotation

The project is focused on proteolytic enzymes of the cathepsin type that are critically involved in pathologies and are therapeutic targets. Cathepsins of human origin and those from pathogens and parasites will be investigated. The aim of the project is to analyze the structure and function of cathepsins and develop novel inhibitory molecules for their regulation. The research in the field of biochemistry and molecular biology employs the following main approaches: functional proteomics and chemical genomics, recombinant protein expression, enzymology, protein crystallography, and molecular modeling

Comprehensive approach to structural analysis of novel polycyclic diterpenes from termites

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Mgr. Pavlína Kyjaková, PhD.

Annotation

Termites are the group of insects with the richest repertoire of defensive chemicals. They are especially famous for the production of roughly one hundred different polycyclic diterpenes with variable topologies of double bonds combined with different oxygenated moieties attached to bi-, tri- and tetracyclic diterpene skeletons. In spite of the extensive quest for new termite diterpenes during the past decades, large part of their structural richness remains undiscovered. The proposed PhD. project focuses on chemical diversity of polycyclic diterpenes in the so-called Subulitermes group of species from South America, in which we recently unveiled an unexpected repertoire of diterpenes structures. The project will address the diterpene diversity as a tool for chemical taxonomy on the one hand, and an opportunity to fully identify structures of new and complex natural compounds on the other hand. The first goal will be to characterize individual species based on combination of characteristic chemical profiles with mitochondrial DNA sequences, to identify new species, to discriminate cryptic species, and ultimately to build phylogenetic hypotheses on their relationships. The knowledge on the overall diterpene diversity will serve as a basis for the second goal of the project, which will combine traditional analytical workflow with modern approaches and computational tools to fully characterize the molecular structures in a maximum of detected diterpenes.

Crystalline sponge method

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Ing. Tomáš Pluskal, Ph.D.

Annotation

Our lab combines cutting-edge experimental (e.g., LC-MS, metabolomics, RNA-seq) and computational (e.g., bioinformatics, molecular networking, machine learning) approaches to develop rapid, generally applicable workflows for the discovery and utilization of bioactive molecules derived from plants. We are looking for talented and motivated chemist with a strong experience in small molecule X-ray crystallography. The successful candidate for this position will be developing protocols for the “crystalline sponge” structure elucidation method and applying them to various plant natural products, particularly terpenes.

Design and synthesis of inhibitors of purine nucleoside phosphorylases – SAR study

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Ing. Zlatko Janeba, Ph.D.

Annotation

We have recently prepared a novel type of acyclic nucleoside phosphonates as potent inhibitors of human purine nucleoside phosphorylase (hPNP). Such compounds may have potential to treat various T-cell leukemias. In order to select suitable candidates for preclinical evaluation, the goal is design and synthesis of a larger amount of derivatives and evaluation of their biological properties. The synthesis of potential PNP inhibitors will be developed and optimized.

Design and synthesis of novel photoswitches derived from heteroarylazobenzenes and bis-azobenzenes

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Ing. Zlatko Janeba, Ph.D.

Annotation

We have recently reported synthesis of variously substituted 5-phenylazopyrimidines (see references for more information). Their physicochemical properties were studied using in situ irradiation NMR spectroscopy and optical spectroscopy. The goal of the current project will be synthesis of novel molecular photoswitches based on a combination of bis-azobenzenes and pyrimidines (and other heterocycles), namely bis(pyrimidinyldiazenyl)benzenes. Their synthesis will be developed/optimized and their physicochemical properties will be studied.

Design and synthesis of novel prodrugs of acyclic nucleoside phosphonates

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Ing. Zlatko Janeba, Ph.D.

Annotation

Acyclic nucleoside phosphonates (ANPs) represent an important class of antiviral agents. The phosphonate group is deprotonated at physiological pH and, thus, ANPs are polar molecules unable to effectively penetrate into cells. Prodrugs of ANPs help to overcome this obstacle. The goal of the project will be design and synthesis of novel prodrugs of ANPs and study of their properties.

Development of new chemical tools to study cell-cell interactions

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Ing. Milan Vrábel, Ph.D.

Annotation

Cell-cell interactions play an important role in a myriad of biological processes. These interactions enable cells to communicate, respond to changes in the environment and are involved in many pathologies including cancer. Despite their importance, our ability to study the molecular details and nature of these interactions is still very limited. In this project, we will employ chemical glycoengineering in combination with biocompatible chemical crosslinking reactions to capture, identify and study biomolecules involved in these interactions. This project aims to elucidate the complexity of cell-cell interactions and shed light on individual proteins involved in the process. The ideal candidate should have interest in organic chemistry, chemical biology and related fields.

Light upconversion nanoparticles for infra red photodynamic therapy of tumors

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: RNDr. Petr Ježek, CSc.

Annotation

For numerous tumor types resistance to long-term monotherapies usually develops. In order to overcome it, we shall develop and photophysically test nanoparticle-based systems for infra red photodynamic therapy. Threrefore, we will study detailes photophysics of nanoparticles, namely luminescence kinetics for upcovversion nanoparticles NaY(Gd)F4:Yb3+(Nd3+)/Er3+(Tm3+), which convert either 980? 650/540 nm or 808?650 nm. All these studies will be conducted in the absence and in the presence of a photosenzitizer in the nanoparticle shell, which creates singlet oxygen upon the desired excitation. The second imaging mode will be enabled for cracking these nanoparticles by NMR or PET. Particle surface engineering will include coating with polymers to achieve the highest energy transfer, immobilization a photosenzitizer to induce optimal singlet oxygen formation, and attachment of addressing peptides to facilitate cell internalization. Chelator for 64Cu or 125I attachment will be also introduced to integrate upconversion luminescence with PET imaging. Singlet oxygen production and pharmacokinetics of the particles on nude mice with xenotransplanted tumors will be also determined. The molecular biology techniques will be conducted by the coworkers of the Department No.75., Inst. Physiology.

Liquid chromatography–mass spectrometry for metabolomics and lipidomics studies

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: doc. Ing. Tomáš Čajka, Ph.D.

Annotation

Over the last decade, mass spectrometry-based metabolomics and lipidomics have become key disciplines for the comprehensive profiling of polar metabolites and complex lipids in biological systems. Liquid chromatography–mass spectrometry (LC–MS) is the preferred technique in metabolomics and lipidomics permitting effective compound separations and detection. However, there is still a lack of sufficient data on the metabolome and lipidome characterizing biofluids (i.e., plasma, serum, urine) and tissues, which can be easily accessible and reused at any time for future studies. The PhD project aims to focus on (i) merging targeted and untargeted metabolomics and lipidomics methods, (ii) standardization of methods, and (iii) extending the breadth and scope of methods for metabolomics and lipidomics studies (e.g., type 2 diabetes, circadian rhythms). The work will be conducted at the Institute of Physiology CAS and financially supported by various grants (GACR, MSMT, AZV).

Mass spectrometry-based metabolomics of biological systems

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Theses supervisor: doc. Ing. Tomáš Čajka, Ph.D.

Annotation

Untargeted metabolomics methods focus on the analysis of all the detectable metabolites in a sample, including chemical unknowns. Liquid chromatography coupled to mass spectrometry (LC-MS) is the preferred technique in metabolomics permitting effective compound separations and detection. However, up to 80% of all detected signals from untargeted profiling represent unknown metabolites. Such a big obstacle in biomedical and biological research hinders meaningful biochemical and pathway interpretations. The PhD project aims to focus on (i) increasing the coverage of spectral libraries used for metabolite annotation, (ii) applying programs for the prediction of ‘unknown’ metabolites, and (iii) using bioinformatics tools for visualization and interpretation of the data obtained within metabolomics studies (e.g., type 2 diabetes, circadian rhythms). The work will be conducted at the Institute of Physiology CAS and financially supported by various grants (GACR, MSMT, AZV).

Modified DNAzymes and DNA origami

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: prof. Ing. Michal Hocek, DSc.

Annotation

We will design and synthesize modified deoxyribonucleoside triphosphates bearing functional groups or ligands for complexation of metals. They will be used for enzymatic synthesis of modified oligonucleotides which will be applied in selection and construction of functional DNAzymes or DNA origami.

Multivalent neoglycoconjugates with therapeutical potential

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie

Annotation

Galectins are animal lectins with affinity to ?-D-galactosides, which in vivo participate in, e.g., cancerogenesis, metastatic processes, immune response to tumorigenesis, and other cancer-related pathologies. The concentration of extracellular galectins in vivo significantly rises in connection with cancer and therefore they may be used as diagnostic markers in many cancer types, such as colorectal carcinoma. Targeted inhibition of extracellular galectins is one of the novel prospective therapeutic approaches to the treatment of pathologies associated with galectin overproduction. A range of recent structure-function studies revealed detailed structural requirements of individual galectins for high-affinity and selective ligands. The avidity of specific glycomimetics to target galectins may be greatly increased by the multivalent presentation. The aim of this work is to synthesize multivalent neoglycoconjugates carrying specific saccharidic ligands or glycomimetics with high selectivity and affinity to target galectins. The inhibition and binding potential of these neoglycoconjugates to galectins, in particular to galectin-1 and -3, will be assayed by in vitro methods of ELISA and surface plasmon resonance (SPR) with recombinant galectins and, later on, with selected cultures of cancer cells.

New deazapurine nucleosides and nucleotides as potential antivirals or cytostatics

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: prof. Ing. Michal Hocek, DSc.

Annotation

We will design and synthesize new modified deazapurine nucleosides, nucleotides and prodrugs as inhibitors of polymerases or other enzymes of nucleotide metabolism, or as ligands (agonists or antagonists) of nucleotide receptors. Selected active compounds will be further optimized in order to identify preclinical candidates for development of potential antiviral or antitumour agents.

New heterocyclic inhibitors of selected protein kinases

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: prof. Ing. Michal Hocek, DSc.

Annotation

We will design and synthesize modified heterocyclic compounds as inhibitors of selected protein kinases that are relevant targets for potential therapeutics of tumours or neurodegenerative diseases. A combination of rational design, synthesis of combinatorial libraries and optimization of hits will be used.

RNA metabolism related to the control of gene expression in the oocyte and embryo.

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Ing. Michal Kubelka, CSc.

Annotation

Fully grown oocyte utilizes only transcripts synthesized during earlier development. Mechanisms of mRNA metabolism in the mammalian oocyte are still far from being fully understood. In the first meiotic division, shortly after nuclear envelope breakdown, translational hotspots develop in the chromosomal area and in a region which previously surrounded the nucleus. This hotspot is controlled by the activity of the mTOR/4F axis. We suppose that the localization of specific mRNAs and their in situ translation is essential for the generation of developmentally competent oocyte. Thus, the objective of the current project is to investigate translation regulation and polysome profiling of the oocyte after NEBD. We will test our hypothesis that translation of specific mRNAs is essential for meiotic progression before first polar body extrusion. This represents a first attempt to unveil novel regulators of mTOR/4F axis and will add substantial information concerning translational control of specific transcripts after NEBD in order to understand molecular physiology of mammalian oocyte. The aims of project: High-throughput translation analysis after resumption of meiosis in the mammalian oocyte. Regulation of the mTOR/eIF4E pathway after nuclear envelope breakdown..Translation and genomic stability in the mammalian oocyte.Main methods: Next Generation Sequencing, biochemistry, molecular biology, FISH.

Role of adhesion-GPCRs during viral infection of mammalian cells

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Mgr. Jan Weber, CSc.

Annotation

The proposed PhD project addresses the possible role of adhesion G protein-coupled receptors (aGPCRs) during viral infection of mammalian cells. The aGPCRs are intriguing class of seven-transmembrane proteins that play important role in neurodevelopment, immune defense and cancer, but their role during viral infection is mostly unexplored. Currently, we recognize 33 members of aGPCRs in humans but majority are orphan receptors with unknown function. We intend to search for specific aGPCR and/or cellular proteins in aGPCRs pathways involved in infections of mammalian cells and characterize their interaction with viral proteins. During postgradual study, student will learn how to work with cell cultures in biosafety level 3, perform proteomic and bioinformatic analyses and siRNA experiments for gene-knockdown in mammalian cells infected with various viruses. Proposed project will broaden our current knowledge about the role of aGPCRs in infections of mammalian cells and if successful, it can identify potential targets for antiviral therapy.

The development and application of organelle-targeted bioorthogonal cleavage reactions

Department: Department of Chemistry of Natural Compounds, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: Ing. Milan Vrábel, Ph.D.

Annotation

Chemical reactions that can be performed under physiological conditions offer unique possibility to manipulate and study biological processes. Our group has a long-term interest in these, so-called, bioorthogonal reactions. They are mainly known as efficient chemical transformations leading to formation of covalent bonds. It has been only recently when the concept was extended to something what is known as bioorthogonal cleavage reactions. The power of this type of reactions is only slowly becoming recognized. In this project, we aim to develop and employ the release reactions, which will enable de-caging of small molecules within specific cellular compartments. We believe that such systems will offer not only a unique possibility to deliver and activate functional molecules within particular subcellular location, but in a broader sense, to shed light on the function of individual cellular organelles. This project combines organic chemistry with modern chemical biology experiments.

The mannose-6-phosphate/insulin-like growth factor 2 receptor as a target for memory enhancement and tumor suppression

Department: Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology
Also available in programme: Biochemie a bioorganická chemie
Theses supervisor: RNDr. Lenka Žáková, Ph.D.

Annotation

Identifying new compounds that effectively improve neurodegenerative disease is an urgent need. It has been recently shown that insulin-like growth factor 2 (IGF2) has an important role in enhancement of memory. IGF2 is a fetal growth factor that has also significant role in mature mammalian brain. The effect of IGF2 as a cognitive enhancer is rapid and persistent, and is mediated by mannose-6-phosphate/IGF2 receptor (M6P/IGF2R). M6P/IGF2R is a large transmembrane glycoprotein that except IGF2 can bind M6P-containing ligands and binding of one ligand may affect the binding another one. Moreover, overexpression of IGF2 plays important role in development of certain tumors and M6P/IGF2R can play a role as a tumor suppressor. This project is focused on (i) production of M6P/IGF2R or its constructs, (ii) preparation of IGF2R selective IGF2 analogues, and (iii) a libraries of small molecule compounds. This work should lead to important clinical applications of new IGF2 analogues.


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