URL study guide
https://studiegids.vu.nl/en/courses/2024-2025/XM_0041Course Objective
The aim is to obtain experience in scientific research including the design and execution of experiments and to critically interpret and reflect on the experimental results. The project will be conducted within the field of “Synthetic Organic and peptide chemistry “or “Structural chemical biology” in one of the following settings: - University or Academic hospital - Research institute - Company The internship can be performed either within the Netherlands or abroad.Course Content
The specific content of the project depends on the associated supervisor(s), available projects on host/location and the timing of the internship, but roughly deals with one of the following areas of research: - Organic small-molecule chemistry: development of efficient synthetic methods for making biologically relevant molecules. The synthetic toolbox that enables us to make small molecules for drug discovery is never ‘complete’, yet continuously expanding. New and efficient synthetic methods/routes are developed for making ‘drug-like’ compounds. Starting from solid theoretical knowledge of organic chemistry, both new multi-component- and cascade-reactions (in which in one step multiple covalent bonds are formed) as well as new conversions using bio-, organic or transition metal catalysis are applied. With such reactions, multiple outcomes are often possible. Using advance spectroscopic techniques, all products are characterized, and subsequently, the reaction can be optimized to one specific product. The scope of the reaction is determined after establishing the ideal conditions for the newly developed reaction and molecular diversity is the primary driver in choosing the products. Finally, to underline the utility of the newly developed reaction, interesting applications are actively pursued. - Organic and peptide chemistry: Ligands that selectively bind to biomolecular targets are a prerequisite for most strategies aiming at the elucidation or modulation of biological processes. The discovery of these ligands can be very challenging. Giving the huge amount of available structural data, known peptide binding epitopes provide a rich source of inspiration for novel ligands. Preorganization of such peptides into their bioactive conformation or the use of rigid peptidomimetic scaffolds have been applied to ensure binding affinity and bioactivity. Notably, there is a lack of approaches for the stabilization of irregular and complex peptide structures. In addition, the design of peptide-derived bioactive compounds is often hampered by their low cellular uptake and biostability. Addressing these challenges, the design of peptide-inspired ligands for an application in proximity-induced chemical reactions and as inhibitors of protein‒protein interactions is pursued. The core techniques applied in corresponding projects include organic synthesis of non-natural amino acids, solid-phase peptide synthesis and/or the biophysical validation of ligand─receptor interactions (e.g. via fluorescence polarization assays). - Structural chemical biology: The interaction networks of biomolecules such as nucleic acids or proteins are crucial for proper cell function. Once imbalanced, a variety of severe diseases can be the result. Here, we focus on key players of various cancers as well as their interaction partners. We will explore their protein-protein
- as well as their protein-DNA complex formation and use small molecules as modifiers of these interactions. We will also determine their interaction mechanisms on atomic level and use this information to optimize the potency of the small molecule modulator. A subset of the following techniques may be used: sub-cloning genes of interest in suitable expression plasmids, heterologously expressing these in bacteria and purifying them via various chromatography techniques. The quality of the resulting proteins will be analyzed using SDS-PAGE and mass spectrometry. With state of the art crystallization techniques we will search for crystallizing conditions and optimize crystal formation. Subsequent X-ray analysis and structure determination will help to optimize small molecule modulators of protein-protein interactions. Attention will be paid to setting up new research/experiments, using state-of-the-art experimental techniques, analyzing experimental results and keeping adequate documentation.
Teaching Methods
Literature review, formulating a research question, conducting experiments, keeping adequate documentation (e.g. lab journal), analyzing data, reporting on results in progress/group meetings, in a written thesis and final presentation within the research group.Method of Assessment
Academic attitude, execution, oral presentation, and written thesisLiterature
Starting literature will be provided by the supervisor. The first 1-2weeks of the traineeship will be spent on literature reading andpreparation for the project.Target Audience
Research variant of mDDS-Synthesis of Drugs, mDDS-Molecular Pharmacology(depending on the subject)Custom Course Registration
The number of internal (VU) internship positions is limited. Candidates are selected based on their motivation letter and CV in an application procedure. See the canvas site “Master Drug Discovery Sciences” for more information regarding this application procedure. Be aware that selection procedures exist for most external positions as well. Before the start of the project an internship agreement has to be signed by all involved parties and the project proposal has to be approved by the VU supervisor via the online internship management system. See the “Master Drug Discovery Sciences Internship manual” for more information on the rules and regulation regarding internships. If after reading the manual you still have questions regarding the process related to internships, admission, approval, etc., please contact the internship coordinator via [email protected].Additional Information
The standard length of a major internship is 42 EC (7 months). Extension up to 60 EC (10 months) can be incorporated as part of the optional part of the master program. Make sure you discuss your personal education plan with your master (track) coordinator well in advance. See the “Master Drug Discovery Sciences Internship manual” for more information (rules, regulations, tips, etc.) on the internship process. This manual can be found on the canvas community “Master Drug Discovery Sciences”.Entry Requirements
Entry requirements with respect to attained courses and number of credits apply. See the Education and Examination regulations and the internship manual Drug Discovery Sciences. For questions, consult the internship coordinator well in advance ([email protected]).Language of Tuition
- English
Study type
- Master