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Photoselective inhibition of protein-protein interactions to study interactomic networks and the development of new therapies

17th national competition for scientific and technical research

Interactome: pathological implications

Senior Researcher : Pau Gorostiza Langa

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Research Centre or Institution : Instituto de Bioingeniería de Cataluña (IBEC). Barcelona.


The manipulation of cellular processes using light by means of optogenetics has revolutionised experimental neurobiology, and use of this technique is expanding to other branches of biology. Optogenetic manipulation of cellular activity is based on the overexpression of photosensitive proteins, which often alter cell physiology and are a therapeutic limitation, given that gene therapy is required in the case of human subjects. Optopharmacology (the development of photoregulated drugs such as agonists, antagonists and modulators) provides a strong alternative to optogenetics, given that it is able to act on endogenic receptors without genetic manipulation. Unlike optogenetics, optopharmacology involves small molecules that can be validated and approved by means of normalised trials for drug development, being a single component that can be applied directly to wild organisms, including humans.

In spite of advances in the development of drugs, many challenges still have to be addressed. These include controlling the place where a drug acts, the duration of its effect and the adjustment of this effect in the target tissue. This proposal covers these questions by using drugs whose affinity or efficacy depends on light, to regulate endogenic protein activity by varying illumination in space and time. We recently developed a new optopharmacological tool, photoregulated peptide inhibitors of protein-protein interactions. This project will optimise its use for endocytosis by the clatrine route, an important process of cellular internalisation. In particular, we will synthesise and characterise a library of photoswitchable peptides to understand their basic principles from an engineering point of view, to achieve optimum control of protein-protein interactions by using light. We will apply these findings to the development of new photoswitchable peptide inhibitors involved in cancer. We will use these molecules to explore optopharmacology applications against melanoma.

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