Objective
At present, most bioactive drugs internalized by live cells are hydrophobic organic molecules that successfully cross lipid barriers but often lack the fine specificity that could be obtained from polypeptides or oligonucleotides. A first goal of this application is therefore to understand the mechanism of internalization of recently discovered cell-permeable peptides and to improve their efficacy. A second goal is to modify the latter peptides in such a way that their internalization by the cells will be followed by their entry into a secretion pathway with the objective to develop compounds that might translocate across the blood brain barrier.
The proposal is primarily focused on two families of peptides that have been shown to translocate across the cell membrane. The Penetratin family is derived from the third helix of the DNA-binding domain of homeoprotein transcription factors and the Transportan family is derived from the fusion of galanin and mastoparan, two peptides involved in cell signalling. Penetratins and Transportans are internalized through a mechanism that differs from classical endocytosis and have been used by several groups to address biologically active hydrophilic cargoes into the cytoplasm and nucleus of live cells. We now want to better understand the mechanism of internalization of these peptides, to develop new vectors and to analyse the structural (size and structure) and biological (secondary effects) limitations of the cargoes that can be internalized.
Starting from established peptidic sequences we shall use a combination of theoretical (molecular modelization) and experimental approaches to analyse how discrete modifications in peptide structure and lipid composition might affect lipid/peptide interactions and modify the internalization and intra-cellular distribution of the peptides. To evaluate their efficacy, the new vectors developed on the basis of the latter structural studies will be linked to biologically active cargoes, primarily active phosphopeptides (e.g. SH2 or SH3 interacting domains). The influence of the structure of the cargoes (length, type, conformation) on their translocation will be defined. Because the vectors are derived from polypeptides with intrinsic biological activity we shall analyse their influence on cellular physiology, in particular on gene expression and on signalling pathways. This will help to define sequences without undesired biological effects.
To evaluate if the vectors can be developed into agents capable of traversing an epithelium we shall start from the recent demonstration that Engrailed, a homeoprotein transcription factor is not only internalized but also secreted in-vitro. The sequence for internalization has been identified and, as expected, corresponds to the third helix of the homeodomain (Penetratin sequence). The sequence for reentry into a secretion pathway differs from the Penetratin sequence but is not yet totally identified. Once identified this sequence will be used to create chimeric polypeptides potentially able to enter a cell and to be secreted by the same cell. The latter polypeptides will be tested for their capability to transport bioactive compounds across an epithelium in-vitro and in vivo.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences cell biology cell signaling
- natural sciences biological sciences biochemistry biomolecules lipids
- medical and health sciences basic medicine physiology
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Coordinator
1348 LOUVAIN-LA-NEUVE
Belgium
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