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Supramolecular Medicine !

RESEARCH

Our research focuses on understanding the self-assembly of peptides and small molecules under physiologically relevant conditions and their function in cellular models. We employ various tools from peptide science (molecules), biophysical chemistry (systems), and cell biology (function) at different levels of complexity, with a special emphasis on characterizing biomolecules and their self-assembly properties. To investigate their cellular behavior, we implement different cellular models, such as differentiated Caco-2 cells in Transwell systems, which allow us to study their uptake, transport, and effects on the gut barrier, as they serve as a model for the small intestine. Another model we use is the SH-SY5Y cell line, widely employed in neuroscience research to study neurodegenerative diseases, neurotoxicity, and neuronal differentiation. Additionally, we conduct real-time wound-healing assays. Recently, we have been working on connecting different cell types as a model for small organs under dynamic conditions to investigate the gut-brain axis.

The final aim is to obtain a profound understanding of the relationship between molecular structure, morphology, and function in biologically relevant environments.

Nowadays, our principal research is directed towards understanding the mechanism of peptide/protein self-assembly and its roles on the delicate balance between health and disease in gluten-related disorder, like celiac disease, non-celiac gluten/wheat sensibility or gluten ataxia. From our investigations, it is clear that gluten peptides are not only pathogenic for celiac patients. They possess interesting molecular and supramolecular features that could be used to disclose the mechanism of cellular uptake and be translated into other pathologies like aggregopathies and even cancer. This translational research is complemented with other more basic projects in the area of protein/peptide-protein interaction, and functional molecules like photoswitchable biosystems.

Gluten related-disorders and Protein-Protein Interaction

Gluten-related disorders are a group of diseases that involve the activation of the immune system triggered by the ingestion of gluten. These disorders have a high prevalence in Western societies around 5% worldwide because gluten is present in wheat, rye, barley, and some varieties of oats.

It is accepted that the incomplete proteolysis of the gluten proteins is responsible for disease in susceptible individuals. From the chemical perspective, up to now, the research efforts focused on the identification, quantification, and separation of the components of gluten and connecting them with their pathological role in vitro and in vivo. Interestingly, while the primary structure of the molecules involved in the disease is known, there is a lack of information about their intrinsic behavior –such as their folding and molecular organization- under physiologically relevant conditions.

Gliadin and its 33-mer fragment have a central pathogenic role in the context of gluten-related. The aim of the present project is to elucidate the molecular, structural, and supramolecular basis of 33-mer oligomerization and the role of the 33-mer nanostructures in the delicate balance between health and disease.

Oligomerization and conformational transition, towards the β- parallel structure, are hallmarks of Alzheimer’s disease, Parkinson’s disease, and prion disease.

Based on these similarities, the relationship between 33-mer accumulations, due to proteolytical resistance, followed by oligomerization can be the up to now unknown trigger of disease before the onset of inflammation. This hypothesis opens new avenues to understand and treat this common pathology.

To prove this hypothesis, we moved from chemical and biophysics to immunological research, reporting for the first time that only large structures of 33-mer induce an innate immune response in macrophages which is mediated by Toll-like receptor (TLR) 4 activation. This result opens the understanding of the early stages of the disease. It connects activation of the innate immune system triggered by the presence of 33-mer protofilaments for the first time.

The current project combines different chemical and biological methodologies and approaches by including peptide chemistry, structural and supramolecular characterization methods, cellular biology approaches, proteomics, and super-resolution optical microscopy. By combining my research expertise and those of my collaborators, it will be possible to quantify and understand the role of the 33-mer oligomers as modulators of disease.

Our findings will open new avenues in the understanding of gluten-related disorders directed towards the design of new prevention and therapeutic targets beyond the gluten-free diet.

Funding: Deutsche Forschungsgemeinschaft (DFG)

Publications

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