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  • Review Article
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Designing peptide receptor agonists and antagonists

Nature Reviews Drug Discovery volume 1, pages 847–858 (2002)Cite this article

Abstract

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.

  • If agonist activity is desired, in many cases the natural peptide can be used as a starting point. Often, the native hormone or neurotransmitter has properties that need to be modified to make it a more effective drug; for example, increasing its stability against proteolysis. In this case, the structure has to be modified so as to enhance the desired properties, while maintaining or even increasing agonist potency.

  • This can be accomplished by using a systematic approach that identifies the structural elements in the peptide that are responsible for its agonist activity (that is, the pharmacophore elements) and then further determines the 3D relationships of these pharmacophore elements for agonist activity (that is, the biologically active conformation). This general approach and examples of its application are discussed.

  • In general, antagonists have different structure–activity relationships than agonists. However, once a lead compound has been found, the general approach for agonists can be applied to antagonists.

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Figure 1: A general strategy for peptide-targeted design of agonists and antagonists of peptide receptors.
Figure 2: Conformations of peptides.
Figure 3: Some peptide 'templates' that can fix or bias conformations.
Figure 4
Figure 5: Side-chain torsional angles (Chi-1; χ1) and χ1/χ2 energy plot for four isomers of β-methyl 2′,6′-dimethyltyrosine.
Figure 6
Figure 7

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Acknowledgements

The science discussed in this review would not have been possible without the creative input and hard work of my students, collaborators and colleagues, and I am eternally grateful for having the opportunity to work with them over the years. The ideas and opinions expressed are mine and are not necessarily those of my students and collaborators, or the agencies and institutions that have supported my research. The long-term support of the National Institutes of Health, USPHS, is gratefully acknowledged. I wish especially to thank M. Colie for her help in putting this review together.

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  1. Department of Chemistry, University of Arizona, 1306 East University Boulevard, Tucson, 85721, Arizona, USA

    Victor J. Hruby

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DATABASES

LocusLink

calcitonin

cholecystokinin

cholecystokinin receptor

endothelin

enkephalin

glucagon

insulin

LHRH

δ-opioid receptor

κ-opioid receptor

μ-opioid receptor

oxytocin

oxytocin receptor

POMC

somatostatin

FURTHER INFORMATION

5z.com/divinfol

Glossary

PRODRUG

A chemically modified drug that is converted to the biologically active compound in vivo.

χ1 GROUP

χ1 is the torsional angle about the Cα–Cβ bond in an amino-acid residue in a peptide or protein.

GEMINAL

Two substituents on the same (geminal) carbon atom.

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Hruby, V. Designing peptide receptor agonists and antagonists. Nat Rev Drug Discov 1, 847–858 (2002). https://doi.org/10.1038/nrd939

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