Protein limitation plays an essential role for membrane recognition and anchoring of proteins. More specifically, cytokine palmitoylation of RAS -a C16 modification of sulphide groups of key player protein in an important signal transudation pathway- is regulated by a recently discovered enzyme -APT1- and the exact role of this process has been a matter of discussion over the last decade. In order to gain insights into this yet unsolved question, I propose to approach the problem in a multidisciplinary fashion by building up a combinatorial library based on a known binder of this protein to increase its inhibitory properties. The new compound can then be used to study the phenotype differences before and after chemically knocking out APT1 and therefore establishing its exact biochemical role within the pathway. The first stage of the project involves use of traditional synthetic methodology to prepare some intermediate benzodiazepines. Secondly, solid phase chemistry will be used to create combinatorial library. Other scientists with whom I will be closely collaborating will use the best compounds in terms of inhibition. The proposed research project aims to shed light on to a long-standing biological problem by meanings of a multidisciplinary approach. The MPI Dortmund is one of the very few places in Europe where such an approach can be pursued. After completing this project, besides increasing the knowledge of the scientific community, Expect to have gained a robust expertise in the solid phase and combinatorial chemistry field, wich are nowadays-paramount areas in drug research.
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