Designing peptide receptor agonists and antagonists

The most ubiquitous mode for controlling and modulating cellular function, intercellular communication, immune response and information-transduction pathways is through peptide–protein non-covalent interactions. Hormones, neurotransmitters, antigens, cytokines and growth factors represent key classes of such peptide ligands. These ligands might either be processed fragments of larger precursor proteins or surface segments of larger proteins. Although there are numerous exceptions, such as insulin, oxytocin and calcitonin, most ligands are not used directly as drugs, and often the most useful ligands for therapy would be analogues that act as antagonists of the native ligands. A search for systematic structure-based or ligand-based approaches to designing such ligands has been an important concern. Today, a robust strategy has been developed for the design of peptides as drugs, drug candidates and biological tools. This strategy includes structural, conformational, dynamic and topographical considerations. Key Points Peptide–macromolecular interactions constitute the main physico-chemical mechanisms by which living processes are controlled and modulated, making the development of peptide or peptide-mimetic ligands that can modulate these activities a top priority in biology and medicine. This Review focuses primarily on peptide hormones and neurotransmitters with targets that are integral membrane proteins, particularly G-protein-coupled receptors (GPCRs). Because GPCRs are integral membrane proteins, it has been difficult to obtain their three-dimensional (3D) structures. Hence, 'structure-based drug design' based on the 3D structure of the target receptor is not generally possible. Nonetheless, robust strategies for peptide ligand design ('ligand-based drug design') have been developed that require careful consideration of both the structural and conformational features of peptides and detailed analyses of their biological activities (binding, second-messenger, tissue and whole-animal assays). In general, for the treatment of disorders that involve peptide (or protein) hormones and transmitters, agonist or antagonist ligands, or more recently, inverse-agonist ligands, are needed. As these three types of ligand bind to different conformational states of GPCRs, it is useful, and often necessary, in considering the design of peptide ligands that target these different receptor states, to consider agonist and antagonist ligands separately, at least initially.