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，通过作为神经递质、神经激素、激素、生长因子或抗生素来调节关键的生理过程。由于多肽具有广泛的功能和高度的特异性和效价，基于多肽的治疗和诊断工具的开发受到了越来越多的关注，要求在分子水平上更好地了解它们的作用机制。为了发挥生物学功能(S)，多肽链需要折叠成一个非常特定的三维结构，称为生物活性结构，从而能够精确定位其药用成分。然而，许多内源性多肽是天然无序的，即它们在溶液中表现出随机卷曲结构。在复杂的生物体系的背景下，尚不清楚如何执行多肽从随机卷曲到明确定义的生物活性构象的构象转变。这种知识的缺乏构成了使用多肽作为治疗药物的一个主要缺陷。这项研究计划的总体目标是阐明生化微环境和分子相互作用组如何影响内在无序多肽的构象格局，并开发创新的基于多肽的疗法和化学工具。我们特别感兴趣的是一个同源的多肽激素家族，它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、食物摄取和血压。然而，过去多肽药物设计的大部分注意力都集中在生物活性构象的阐明上，而多肽配体与细胞表面微环境之间的相互作用的意义和影响却没有得到解决。该计划将重新定义瞬时结合伙伴在这些天然紊乱的多肽激素的生物活性中的作用。我们的结果可能导致开发一类具有治疗潜力的新分子，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.