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

多肽是一类重要的生物大分子，通过充当神经递质、神经激素、激素、生长因子或抗生素来调节关键的生理过程。由于多肽的多种功能和高特异性和效力，基于多肽的治疗和诊断工具的发展受到越来越多的关注，要求在分子水平上更好地了解其作用机制。为了发挥其生物学功能，多肽链需要折叠成非常特定的三维结构，即生物活性结构，从而可以精确定位其药效成分。然而，许多内源性肽是天然紊乱的；即它们在溶液中表现为随机线圈结构。目前尚不清楚，在复杂的生物系统中，肽的构象是如何从随机线圈转变为明确定义的生物活性构象的。这种知识的缺乏构成了使用肽作为治疗手段的主要缺陷。本研究计划的总体目标是阐明生化微环境和分子相互作用如何影响内在无序肽的构象景观，并开发创新的基于肽的治疗方法和化学工具。我们对同质的肽激素家族特别感兴趣，它们通过与膜结合受体的特异性结合来调节重要的生理反应，如中枢神经系统的个体发生、食物摄入和血压。然而，以往肽类药物设计的大部分注意力都集中在阐明其生物活性构象上，而肽类配体与细胞表面微环境之间相互作用的重要性和影响尚未得到解决。这个程序将重新定义瞬时结合伙伴在这些天然紊乱肽激素的生物活性中的作用。我们的研究结果可能会导致一类具有治疗潜力的新分子的发展，这些分子可用于治疗各种疾病，如自闭症、骨质疏松症和神经损伤。

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.