Molecular determinants of cellular penetration and permeability

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The proposed research program broadly aims to identify, with the help of designed molecules, the fundamentals of cellular internalization and cellular permeability. It is composed of 2 themes.******In Theme I, we will design and synthesize modular guanidine-rich transporters (GRT) aimed to probe and understand the chemical space defined by the cellular membrane. Indeed, the latter is the first environment that molecules meet prior to be internalized by cells. However, its structure and interactions with molecules is poorly characterized. Thus, we will vary the structure of cellular penetration vectors to probe this environment, in order to refine efficacious, stable cellular penetration vectors. We will study cellular internalization mechanims using Fluorescence-Activated Cell Sorting, and their intracellular distribution using confocal microscopy. We will also study their cellular selectivity properties, with the goal to understand structure-selectivity relationship. This knowledge is important to subsequently engineer molecules able to specifically deliver cargos (drugs, imaging agents) specifically to a site of interest.******In Theme II, we will study the structure-permeability relationship of semi-peptidic macrocycles. As opposed to purely peptidic macrocycles, semi-peptidic ones have not been investigated for their permeability properties. Our preliminary results indicate that subtle structural variations, via simple methylation at selected positions, deeply influence cellular permeability. It should be kept in mind that macrocycles emerge as privileged structures for the modulation of protein-protein interactions, an ensemble of several hundred thousand potential targets for which small molecules have performed very poorly. Understanding their permeability and how to optimize it is critical for these molecules to be efficacious on these intracellular targets.******Both themes are at the extremes of the structure-permeability continuum, and will provide critical knowledge that will contribute to better develop practical solutions to optimize smarter drugs.