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KOSK-II-Katalyse og org.synt.kjemi II

Structure-Activity Relationship and Binding Mode for Cyclopentapeptide Antagonists of CXCR4, a Therapeutic Target in HIV/AIDS and Oncology

Tildelt: kr 2,9 mill.

The main physiological role of the human G-protein coupled chemokine receptor CXCR4 and its natural ligand SDF-1a is homing of leukocytes and embryonic development. However, CXCR4 has also been shown to be involved in the pathology of several serious dise ases, most notably AIDS (HIV entry point in T-cells) and cancer (angiogenesis and metastasis). Consequently, CXCR4 antagonists have emerged as a promising class of drugs. The primary objective of this project is to establish the structure-activity relatio nship and binding mode for cyclopentapeptide CXCR4 antagonists in order to facilitate the future design and synthesis of novel peptidomimetic CXCR4 antagonists with therapeutic potential. As for most other GPCRs, the experimental structure of the human CXCR4 receptor has not been elucidated. In the absence of target structure, rational development of novel antagonists relies on ligand-based design, i.e. the information obtained from active and inactive ligands in structure-activity studies. Accordingly, the foundation of this project is the design and synthesis of semi-rigid cyclopentapeptide ligands that will be tested for affinity for wild-type CXCR4 and designed CXCR4-mutants in order to deduce the structural properties of the complementary CXCR4 bin ding site. The experimental data combined with computational studies (pharmacophore modeling, homology modeling and docking) is expected to result in detailed insight into the structure-activity relationship and binding mode of cyclopentapeptide ligands. This information will in turn facilitate rational development of novel peptidomimetic CXCR4 antagonists with therapeutic potential.

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KOSK-II-Katalyse og org.synt.kjemi II