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Review
. 2013:53:557-80.
doi: 10.1146/annurev-pharmtox-010510-100456.

Design of peptide and peptidomimetic ligands with novel pharmacological activity profiles

Victor J Hruby  1 , Minying Cai
Affiliations
Review

Design of peptide and peptidomimetic ligands with novel pharmacological activity profiles

Victor J Hruby et al. Annu Rev Pharmacol Toxicol. 2013.

Abstract

Peptide hormones and neurotransmitters are of central importance in most aspects of intercellular communication and are involved in virtually all degenerative diseases. In this review, we discuss physicochemical approaches to the design of novel peptide and peptidomimetic agonists, antagonists, inverse agonists, and related compounds that have unique biological activity profiles, reduced toxic side effects, and, if desired, the ability to cross the blood-brain barrier. Designing ligands for specific biological and medical needs is emphasized, as is the close collaboration of chemists and biologists to maximize the chances for success. Special emphasis is placed on the use of conformational (ϕ-ψ space) and topographical (χ space) considerations in design.

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Figures

Figure 1
Figure 1
Conversion of enkephalin into potent and δ opioid receptor-selective ligands.
Figure 2
Figure 2
Structure of β-methyl-2′,6′-dimethyltyrosine (trimethyltyrosine, TMT) and its low-energy side-chain gauche conformations for the 2S,3R isomer.
Figure 3
Figure 3
Use of c[D-Pen2, D-Pen5]enkephalin (DPDPE) and [2S,3R]TMT1-DPDPE to design a nonpeptide peptide mimetic for the δ opioid receptors.
Figure 4
Figure 4
Converting somatostatin-14 to a highly potent μ opioid receptor-selective antagonist.
Figure 5
Figure 5
Development of novel analogs of α-MSH with novel biological activity profiles. Abbreviations: α-MSH, α melanocyte-stimulating hormone; MC, melanocortin; MT, melanotan; NDP-α-MSH, [Nle4,D-Phe7]α-MSH.
Figure 6
Figure 6
Structure of glucagon.
See this image and copyright information in PMC

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