Probing the molecular mechanisms of action of class B G protein-coupled receptor peptide ligands: a multidisciplinary study.

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Peptides are an important class of biological macromolecules that regulate key physiological processes by acting as neurotransmitters, neurohormones, hormones, growth factors or antibiotics. Owing to the large array of functions and high specificity and potency of peptides, the development of peptide-based therapeutic and diagnostic tools has received an increased interest, demanding for a better understanding of their mechanisms of action at the molecular level. To perform its biological function(s), a polypeptide chain needs to fold into a very specific three-dimensional structure, known as the bioactive structure, allowing the precise positioning of its pharmacophoric elements. However, numerous endogenous peptides are natively disordered; i.e. they exhibit a random coil structure in solution. It is not understood, in the context of a complex biological system, how the conformational shift of a peptide from a random coil into a well-defined biologically active conformation is performed. This lack of knowledge constitutes a major drawback for the use of peptide as therapeutics. The overarching goals of this research program are to elucidate how the biochemical microenvironment and the molecular interactome influence the conformational landscape of intrinsically disordered peptides and to develop innovative peptide-based therapeutics and chemical tools. We are particularly interested in a homogenous family of peptide hormones, which through specific binding to membrane-bound receptor regulate important physiological responses, such as central nervous system ontogenesis, food intake and blood pressure. Whereas most of the past attention in peptide drug design has been focusing on the elucidation of the bioactive conformation, the significance and the impact of the interactions between the peptidic ligands and the cell surface microenvironment have not been addressed. This program will redefine the roles of transient binding partners in the biological activity of these natively disordered peptide hormones. Our results could lead to the development of a new class of molecules having therapeutic potential for the treatment of various diseases such as autism, osteoporosis and neurological insults.